11-(2-Hydroxyethylthio)prostenoic acid E series derivatives

ABSTRACT

This disclosure describes certain 11-(2-hydroxyethylthio)-9-keto-prostenoic acid E series derivatives, and their intermediates, useful as bronchodilators and inflammatory medeator release inhibitors.

This is a division, of application Ser. No. 782,853, filed Mar. 30,1977, now U.S. Pat. No. 4,085,272.

BACKGROUND OF THE INVENTION

Applicants are not aware of any prior art references which, in theirrespective judgments as one skilled in the prostaglandin art, wouldanticipate or render obvious the novel compounds of the instantinvention; however, for the purpose of fully developing the backgroundof the invention and establishing the state of the requisite art, thefollowing reference is set forth: U.S. Pat. No. 3,876,690, whichdiscloses certain 11-(2-hydroxyethoxy)-9-keto and 9-hydroxy-prostenoicacid derivatives.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel11-(2-hydroxyethylthio)13-trans-prostenoic acids and esters as well asto the cyclopentenone intermediates and processes for their preparation.The novel compounds of this invention embrace all the possible opticalisomers, diastereomers and enantiomers, racemates, and racemic mixturesrepresented by the following general formulae of the naturally occurringmammalian prostaglandins.

The first embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR1## wherein Z is a divalent moietyselected from the group consisting of --(CH₂)₆ -- and ##STR2## R₁ isselected from the group consisting of hydroxy and C₁ -C₆ alkoxy; and Ris a moiety selected from the group consisting of ##STR3## wherein R₄ isselected from the group consisting of hydrogen and methyl, R₅ isselected from the group consisting of C₄ -C₇ alkyl and 2-cis(C₄-C₆)alkenyl, R₆ is selected from the group consisting of C₃ -C₅ alkyl,R₈ is selected from the group consisting of C₁ -C₂ alkyl, and R₁₁ isselected from the group consisting of C₃ -C₇ alkyl; with the provisothat when R₅ is 2-cis(C₄ -C₆)-alkenyl, then R, must be hydrogen and Zmust be ##STR4## the racemic mixture thereof; the mirror image thereof;and when R₁ is hydroxy, the pharmaceutically acceptable salts thereof.

A preferred embodiment of the first embodiment consists of thosecompounds wherein Z, R and R₁ are as previously defined; and thesubstituent at the carbon-11 position is β-(2-hydroxyethylthio).

A second preferred embodiment of the first embodiment consists of thosecompounds wherein Z, R and R₁ are as previously defined; and thesubstituent at the carbon-11 positon is α-(2-hydroxyethylthio).

A most preferred embodiment of the second preferred embodiment consistsof those compounds wherein Z and R₁ are as previously defined; and R isa moiety selected from the group consisting of ##STR5## wherein R₄ andR₅ are as previously defined.

A second most preferred embodiment of the second preferred embodimentconsists of those compounds wherein Z and R₁ are as previously defined;and R is a moiety selected from the group consisting of ##STR6## whereinR₆, R₈ and R₁₁ are as previously defined.

The second embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR7## wherein Z is a divalent moietyselected from the group consisting of --(CH₂)₆ -- and ##STR8## R₁ isselected from the group consisting of hydroxy and C₁ -C₆ alkoxy; and Ris a moiety selected from the group consisting of ##STR9## wherein R₆ isselected from the group consisting of C₃ -C₅ alkyl, R₇ is selected fromthe group consisting of C₂ -C₄ alkyl, R₁₀ is selected from the groupconsisting of C₁ -C₄ alkyl, R₁₁ is selected from the group consisting ofC₃ -C₇ alkyl and R₁₂ is selected from the group consisting of C₁ -C₃alkyl; the racemix mixture thereof; the mirror image thereof; and whenR₁ is hydroxy, the pharmaceutically acceptable salts thereof.

A preferred embodiment of the second embodiment consists of thosecompounds wherein Z, R and R₁ are as previously defined; and thesubstituent at the carbon-11 position is β-(2-hydroxyethylthio).

A second preferred embodiment of the second embodiment consists of thosecompounds wherein Z, R and R₁ are as previously defined; and thesubstituent at the carbon-11

A most preferred embodiment of the second preferred embodiment consistsof those compounds wherein Z and R₁ are as previously defined; and R isa moiety selected from the group consisting of ##STR10## wherein R₆,R₁₀, R₁₁ and R₁₂ are as previously defined.

A second most preferred embodiment of the second preferred embodimentconsists of those compounds wherein Z and R₁ are as previously defined;and R is a moiety selected from the group consisting of ##STR11##wherein R₇ is as previously defined.

A still further preferred embodiment of the second most preferredembodiment consists of those compounds wherein Z and R₁ are aspreviously defined; and R is ##STR12## wherein R₇ is as previouslydefined.

A still further preferred embodiment of the first Z and R₁ are aspreviously defined; and R is a moiety selected from the group consistingof ##STR13##

A second still further preferred embodiment of the first most preferredembodiment consists of those compounds wherein Z and R₁ are aspreviously defined; and R is a moiety selected from the group consistingof ##STR14##

The third embodiment of the invention is represented by an opticallyactive compound of the formula: ##STR15## wherein Z is a divalent moietyselected from the group consisting of --(CH₂)₆ -- and ##STR16## R₁ isselected from the group consisting of hydroxy and C₁ C₆ alkoxy; and R isa moiety selected from the group consisting of ##STR17## wherein R₆ isselected from the group consisting of C₃ -C₅ alkyl, R₈ is selected fromthe group consisting of C₁ -C₂ alkyl and R₁₁ is selected from the groupconsisting of C₃ -C₇ alkyl; the racemic mixture thereof; the mirrorimage thereof; and when R₁ is hydroxy, the pharmaceutically acceptablesalts thereof.

A preferred embodiment of the third embodiment consists of thosecompounds wherein Z, R and R₁ are as previously defined; and thesubstituent at the carbon-11 position is β-(2-hydroxyethylthio).

A second preferred embodiment of the third embodiment consists of thosecompounds wherein Z, R and R₁ are as previously defined; and thesubstituent at the carbon-11 position is α-(2-hydroxyethylthio).

A most preferred embodiment of the second preferred embodiment consistsof those compounds wherein R₁ and Z are as previously defined; and R isa moiety selected from the group consisting of ##STR18## wherein R₁₁ isas previously defined.

An optically active compound according to Claim 66, wherein R₁ and Z areas previously defined; and R is a moiety selected from the groupconsisting of ##STR19## wherein R₆ and R₈ are as previously defined.

The fourth embodiment of the invention is represented by a compound ofthe formula: ##STR20## wherein Z is a divalent moiety selected from thegroup consisting of --(CH₂)₆ -- and R₁ is selected from the groupconsisting of hydroxy, C₁ -C₆ alkoxy, trityloxy, tetrahydropyranyloxyand tri-(C₁ -C₆)alkylsilyloxy; and R₂ is selected from the groupconsisting of hydrogen, trityl, tetrahydropyranyl and tri-(C₁-C₆)alkylsilyl.

A preferred embodiment of the fourth embodiment consists of thosecompounds wherein R₁ and R₂ are as previously defined; and Z is##STR21##

A most preferred embodiment of the preferred embodiment consists ofthose compounds wherein Z is as previously defined; R₁ is selected fromthe group consisting of hydroxy, C₁ -C₆ alkoxy and tri(C₁-C₆)alkylsilyl; and R₂ is selected from the group consisting of hydrogenand tri(C₁ -C₆)alkylsilyl.

Useful pharmacologically acceptable salts of the above formula, where R₁is hydroxyl, are those with pharmacologically acceptable metal cations,ammonium, amine cations or quaternary ammonium cations.

Preferred metal cations are those derived from the alkali metals, e.g.lithium, sodium and potassium, and from the alkaline earth metals, e.g.magnesium and calcium, although cationic forms of other metals, e.g.aluminum, zinc and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary or tertiary amines such as mono-, di- ortrimethylamine, ethylamine, dibutylamine, triisopropylamine,N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine,cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, α- orβ-phenylethylamine, ethylenediamine, diethylenetriamine, and araliphaticamines containing up to and including 18 carbon atoms, as well asheterocyclic amines, e.g., piperidine, morpholine, pyrrolidine,piperazine and lower alkyl derivatives thereof, e.g. 1-methylpiperidine,4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine,1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well asamines containing water-solubilizing or hydrophilic groups e.g. mono-di- or triethanolamine ethyldiethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxy-methyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium and the like.

The compounds of this invention are administered in various ways forvarious purposes, e.g., intravenously, intramuscularly, subcutaneously,orally, intravaginally, rectally, bucally, sublingually, topically andin the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose it is preferred, because ofincreased water solubility, that R₁ be hydrogen or a pharmacologicallyacceptable cation. For subcutaneous or intramuscular injection, sterilesolutions or suspensions of the acid, salt, or ester form in aqueous ornon-aqueous media are used. Tablets, capsules, and liquid preparationssuch as syrups, elixirs, and simple solutions, with the usualpharmaceutical carriers are used for oral or sublingual administration.For rectal or vaginal administration, suppositories prepared as known inthe art are used. For tissue implants, a sterile tablet or siliconerubber capsule or other object containing or impregnated with thesubstance is used. On certain occasions it may be advantageous toadminister the compounds of this invention as clathrate compounds withsubstances such as α-cyclodextrin.

DETAILED DESCRIPTION OF THE INVENTION

The prostaglandins are a family of closely related tissues and whichstimulate smooth muscle, lower arterial blood pressure, antagonizeepinephrine-induced mobilization of free fatty acids, and have otherpharmacological and autopharmacological effects in mammals. SeeBergstom, et. al., J. Biol. Chem., 238, 3555 (1963) and Horton,Experientia, 21, 113 (1965) and references cited therein. All of the socalled natural prostaglandins are derivatives of prostanoic acid:##STR22## The hydrogen atoms attached to C-8 and C-12 are intransconfiguration. The natural prostaglandins represent only one of thepossible optical isomers. The compounds of this invention include allpossible optical isomers and racemates.

The configuration of substituents on the prostaglandin molecule aredesigned to be in the α-configuration if they lie beneath the plane ofthe molecule as drawn above and are designated with a ---- bond. Thosesubstituents which lie above the plane of the molecule as drawn aboveare designated β and are represented by a bond. ##STR23##

The natural PGE₁, PGE₂ and PGE₃ compounds are potent in causing multiplebiological responses, even at low doses. As a bronchodilator, thenatural prostaglandins have an inconveniently short duration ofactivity. In striking contrast, the novel11-deoxy-11α/β-(2-hydroxyethylthio) PGE analogs of this inventionpossess a significantly longer duration of bronchodilation in the guineapig Konzett assay.

Bronchodilator activity is determined in guinea pigs againstbronchospasms elicited by intravenous injections of 5-hydroxytryptamine,histamine of acetylcholine by the Konzett procedure. [See J. Lulling, P.Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995(1968)].

In the Table I which follows, bronchodilator activity for representativecompounds of this invention against one or more of the three spasmogenicagents is expressed as an ED₅₀ determined from the results obtained withthree logarithemic cumulative intravenous doses.

                                      TABLE I                                     __________________________________________________________________________    Compound             ED.sub.50 in mg/kg                                         Tested             5-HT                                                                              HIST.                                                                             ACH.                                                                              Potency (Range 0-4)                          __________________________________________________________________________    1-11α,β-(2-hydroxyethylthio)-11-deoxy-                                                  8.8.sup.-3                                                                        4.24.sup.-3                                                                       27.5.sup.-3                                      PGE.sub.2 methyl ester (Example 223)                                                                   44.2.sup.-3                                                                       391.sup.-3                                                                        4                                            1 11α-(2-hydroxyethylthio)-11-deoxy-                                                         5.9.sup.-3                                                                        4.87.sup.-3                                                                       11.1.sup.-3                                      PGE.sub.2 methyl ester (Example 229)                                                               35.sup.-3   4                                            1 11β-(2-hydroxyethylthio)-11-deoxy-                                                          60.sup.-3                                                                         45.5.sup.-3                                                                       62.8.sup.-3                                      PGE.sub.2 methyl ester (Example 229)                                                                       671.sup.-3                                                                        4                                            1 11;60 /β-(2-hydroxyethyltho)-11,deoxy-                                                      5.5.sup.-3                                                                        4.7.sup.-3                                                                        11.sup.-3                                        PGE.sub.1 (Example 228)                                                                            34.sup.-3                                                                         36..sup.-3                                                                        61.sup.-3                                                             78.sup.-3                                                                         71.sup.-3                                                                         221.sup.-3                                                                        4                                            d1 11α/β-(2-hydroxyethylthio)-11,15-                                                    19.sup.-3                                                                         19.5.sup.-3                                                                       53.sup.-3                                        bisdeoxy-16-hydroxy-PGE.sub.1 (Example 226)                                                        82.sup.-3                                                                         150.sup.-3                                                                288.sup.-3  3                                            d1 11α/β-(2-hydroxyethylthio)-11,15-                                                    17.sup.-3                                                                         20.sup.-3                                                                         34.sup.-3                                        bisdeoxy-16-hydroxy-16-methyl-PGE.sub.2                                                            77.sup.-3                                                                         108.sup.- 3                                          (Example 225)        257.sup.-3  3                                            __________________________________________________________________________

In addition, compounds of this invention possess the additional abilityto function as inflammatory medeator release inhibitors as assayed usingsensitized human basophiles.

The novel compounds of the present invention can be readily preparedfrom certain PGA derivatives which may be represented by the followinggeneral formula: ##STR24## wherein R, R₁, and Z are as hereinabovedescribed.

The preparation of the requisite PGA intermediates from thecorresponding PGE compounds is described [Corey, E. J., Jour. Amer.Chem. Soc., 90, 3245 (1968)], or can be obtained by analogous proceduresto those described in the aforesaid reference.

The 11-(2-hydroxyethylthio)-prostenoic acids and esters of thisinvention may be prepared by addition of 2-mercoptoethanol to the PGAderivative in the presence of a catalytic amount of an organic base suchas triethylamine. In the absence of a catalysis, the reaction proceedsslowly. The product is obtained as a mixture of epimers at C-11 whichare readily separable by column chromatography on silica-gel.

It has been found, however, if the amount of catalysis is increased, orthe reaction temperature is increased, or the duration of the reactionis increased, then the 11α-isomer product will predominate over the11β-isomer.

The novel compounds of this invention can also be prepared by1,4-conjugate addition involving treatment of the ether blockedcyclopentenone (71) with a lithio-cuprate reagent such as (68), (69), or(70) prepared as illustrated in Flowsheets A through H.

The 1,4-conjugate addition procedure is described hereinbelow inFlowsheet H. The preparation of the various requisite1-iodo-trans-1-alkenyl or 1-tributylstannyl-trans-1-alkenyl derivativeis illustrated in Flowsheets A through F and the novel and importantsynthesis of 4-(2-hydroxyethylthio)-cyclopentenone is described inconnection with Flowsheet G. ##STR25##

In accordance with the scheme as outlined hereinabove in Flowsheet A,carbethoxycyclobutane is converted to its enloate anion (2) by treatmentwith a strong base such as lithium cyclohexylisopropylamide, preparedfrom the corresponding amine and n-butyl lithium (hexane solution) in asolvent, such as anhydrous tetrahydrofuran, at very low temperatures,such as 78° C. The resulting enolate anion (2) is then alkylated withR₁₁ -X (3) to provide (4), the ester group of which is reduced toalcohol (5) by reaction with 2 equivalents of diisobutyl aluminumhydride, lithium aluminum hydride or the like. Oxidation of alcohol (5)with dipyridine chromium oxide complex ["Reagents for OrganicSynthesis", L. F. Fieser and M. Fieser, John Wiley and Sons, Inc., NewYork, 4, 215 (1974)], prepared in situ in methylene chloride solution,provides the corresponding aldehyde (6), which can also be obtaineddirectly from ester (4) by partial reduction with one equivalent ofdiisobutyl aluminum hydride at -78° C., but the former two-stepprocedure is preferable. Reaction of aldehyde (6) with lithium acetylideethylene diamine complex provides the 3-hydroxy-1 -alkyne (7), which isconverted to its trimethylsilyl ether in the usual manner. The silylatedderivative is then treated with disiamylborane (prepared in situ intetrahydrofuran solution at ice bath temperatures from2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate)and then anhydrous trimethylamine oxide. The resulting solution and aniodine solution in tetrahydrofuran are then added simultaneously to anaqueous solution of sodium hydroxide to give the1-iodo-3-trimethylsilyloxy-4,4-trimethylene-1-alkene (8). ##STR26##

In accordance with the scheme as outlined hereinabove in Flowsheet B,1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne (9) is treated withn-butyllithium at -78° C. and then with a freshly prepared solution ofzinc iodide in anhydrous tetrahydrofuran, also at -78° C. Reaction ofaldehyde (10) with the resulting reagent then provides the4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11). This reaction procedeswith great stereoselectivity and the product (11) is in the erythroconfiguration. [For additional information concerning this reaction seethe examples which follow and F. Mercier, R. Epstein and S. Holland,Bull. Soc. Chim. France, 690 (1972)].

The tetrahydropyranyl group in (11) is removed on weak acid treatmentand the resulting erythro diol (12) can be reblocked by treating with anappropriate aldehyde or ketone ##STR27## in the presence of strong acidcatalyst in the usual way to give the ketal or acetal (13). Acetone is auseful ketone for this purpose and the product (13) is then a3,4-isopropylidenedioxy-1-alkyne. It is also possible to utilize silylblocking groups (introduced after removal of the 1-trimethylsilyl group)to ultimately give the vinyl iodides (16) or (17). Weak base treatmentof (13), for example heating for about one hour in refluxing methanolwith potassium carbonate, results in desilylation to give (14). The1-alkene (14) is converted to the corresponding 1-iodo-trans-1-alkene(15) by treatment with disiamylborane (prepared in situ intetrahydrofuran solution at ice bath temperatures from2-methyl-2-butene, sodium borohydride and boron trifluoride etherate)and then anhydrous trimethylamine oxide. The resulting solution and aniodine solution in tetrahydrofuran are then added simultaneously to anaqueous solution of sodium hydroxide to give (15).

For the preparation of the threo derivatives, the4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11) is acetylated to providethe corresponding 4-acetoxy derivative (18). The tetrahydropyranyl groupis preferentially hydrolyzed with weak acid to (19), which is thentosylated in the usual manner to afford theerythro-3-tosyloxy-4-acetoxy-1-alkyne (20). Solvolysis of (20) underessentially neutral conditions by heating in aqueous tetrahydrofuran inthe presence of an insoluble acid-acceptor, such as calcium carbonate,results in inversion of C₃, furnishing thethreo-3-hydroxy-4-acetoxy-1-alkyne (21), which is then deblocked withaqueous base to give the threo-3,4-diol (22). Diol (22) is converted toan acetal or ketal (23) (or silyl derivatives as in (16) or (17)] andthence to the 1-iodo-trans-1-alkene (16) as described hereinabovewherein Ra is lower alkyl (C₁ to C₃).

For the preparation of the 16-alkoxyprostanoic acids of this invention,the erythro-4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11) isdesilylated by methanol-potassium carbonate treatment and the resulting(25) is etherified to give the 4-alkoxy-3-tetrahydropyranyloxy-1-alkyne(26). A useful procedure for this last step involves treatment of (25)with a molar equivalent of sodium hydride to give the 4-alkoxide whichis then alkylated with the appropriate alkylating agent, for examplemethyl iodide. The 4-alkoxy-1-alkyne (26) is then converted to thecorresponding 1-iodo-trans-1-alkene (27) as described hereinabove forthe preparation of (15). If desired the tetrahydropyranyl blocking groupin (27) can be hydrolyzed (weak acid) and the resulting free 3-olcorresponding to (27) converted to the 3-trimethylsilyloxy derivative(28), all in the usual manner wherein R₈ is lower alkyl (C₁ to C₃).

For the threo series, the tetrahydropyranyl group inerythro-4-alkoxy-1-alkyne (26) is cleaved and the resulting3-hydroxy-4-alkoxy-1-alkyne (29) is tosylated to give theerythro-3-tosyloxy-4-alkoxy-1-alkyne (30). S_(n) 2 displacement reactionwith (30) with reagents such as tetrahydroammonium formate results ininversion to the threo derivative (31) saponification of which providesthreo-3-hydroxy-4-alkoxy-1-alkyne (32). Trimethylsilylation followed bythe vinyl iodide conversion procedure described hereinabove furnishesthe threo-1-iodo-1-alkene (33) wherein R₈ is hydrogen or lower alkyl (C₁to C₃).

The 15-alkyl and/or 16-alkyl derivatives of this invention can beprepared by substituting (CH₃)₃ ##STR28## for (4) and/or ##STR29## for(6) (R'₅ =lower alkyl of 1 to 3 carbons) in Flowsheet B.

In accordance with the procedure as outlined in Flowsheet C, an aldehyde(34) is treated with propargylic magnesium halide to form thehomopropargylic alcohol (35), which is converted to its trimethylsilylether in the usual manner. The silylated derivative is then treated withdisiamylborane (prepared in situ in tetrahydrofuran solution at ice bathtemperature from 2-methyl-2-butene, sodium borohydride and borontrifluoride etherate) and then anhydrous trimethylamine oxide. Theresulting solution and an iodine solution in tetrahydrofuran are thenadded simultaneously to an aqueous solution of sodium hydroxide to givethe 1-iodo-4-trimethylsilyloxy-trans-1-alkene (36), precursors for16-hydroxy-prostaglandin.

The trimethylsilyl protecting group is removed with mild acid and theresulting vinyl iodide alcohol is oxidized with pyridiniumchlorochromate to provide the 1-iodo-4-oxo-trans-1-alkene (37), whichupon treatment with a Grignard reagent (R₁₂ MgX) provides the1-iodo-4-hydroxy-trans-1-alkene, which is silylated in the usual mannerto provide the silyl ether (38) wherein R₁₁ is lower alkyl (C₃ to C₇)and R₁₂ is vinyl or cyclopropyl. ##STR30##

A more preferred method for the preparation of vinyllithium precursor isalso described in Flowsheet C. Treatment of the requisite carboxylicacid (39a or 39) with the appropriate organolithium reagent (R₁₂ Li orR₁₁ Li respectively), wherein R₁₁ and R₁₂ are hereinabove define, givethe corresponding ketone (40) which upon treatment with propargylicmagnesium halide provides the homopropargylic alcohol (41) which isconverted to the trans vinylstannyl derivative by sequential treatmentwith chlorotrimethylsilane and tri-n-butyltin hydride. Treatment of thevinylstannyl reagent (42) with n-butyllithium at a temperature of -10°C. to -78° C. generates the corresponding vinyllithium reagent.##STR31##

In accordance with Flowsheet D hereinabove, the precursors for other16-hydroxy prostaglandins are prepared by treating an appropriatealdehyde or ketone (43) with a propargylic magnesium halide to yield therequisite homopropargylic alcohol (44). The alcohol is protected as atritylether (45) (for secondary alcohols) or as a trimethylsilylether(45) (for tertiary alcohols). These ethers are then converted to theappropriate trans-vinyliodide (46) by treatment with disiamylboranegenerated in situ from 2-methyl-2-butene, sodium borohydride, and borontrifluoride, follwoed by treatment with trimethylamine oxide and theniodine and sodium hydroxide, wherein R₁₃ is hydrogen and methyl, T isO--C(C₆ H₅)₃ when R₁₃ is hydrogen and T is O--Si(CH₃)₃ when R₁₃ ismethyl; R₁₄ is selected from the group comprising lower alkyl (C₃ toC₅), lower 1-alkenyl (C₃ to C₅), ##STR32## wherein R₇ is as describedabove; with the provision that when R₁₄ is ##STR33## then R₁₃ must behydrogen. ##STR34##

The preparation of the precursors for the synthesis of 16-aryloxy and17-phenyl congeners is described in accordance with Flowsheet Ehereinabove. The aryl esters (49) are prepared by esterifying thecommercially available acids or by treatment of ethyl bromoacetate withthe appropriate phenol. The ester (49) is carefully reduced to thealdehyde (50) which upon treatment with lithium acetylide provides thepropargylic alcohol (51). Treatment of the alcohol (51) withchlorotrimethylsilane followed by tri-n-butyltin hydride furnishes therequisite vinylstannyl derivative (53). Similar treatment starting withsubstituted hydrocinnamaldehyde (50a) provides the respectivevinylstannyl derivative (53a).

The preparation of the precursors for the synthesis of secondary15-hydroxy congeners are described in the literature. The preparation ofthe precursor for 15-methyl-15-hydroxy is described in Flowsheet Fhereinbelow. In accordance with Flowsheet F, an acid chloride, whereinR₅ is hereinabove defined, is treated with acetylene and aluminumtrichloride to provide the vinylchloride (55) which upon treatment withsodium iodide furnishes the vinyliodide (56). Treatment of (56) withmethylmagnesium halide followed by chlorotrimethylsilane gives therequisite protected vinyliodide (57). ##STR35##

Certain of the requisite 4-(2-hydroxyethylthio)-cyclopentenones may beprepared from the corresponding 4-hydroxy or alkoxy cyclopentenones Iain accordance with the reaction scheme of Flowsheet G or from the3-hydroxy cyclopentenones Ib, also described in Flowsheet G.

The requisite 4-alkoxy cyclopentenones are described in U.S. Pat. No.3,876,690 or can be obtained by analogous procedures to those describedin the aforesaid patent. The 3 and 4-hydroxy-cyclopentenones aredescribed in U.S. Pat. Nos. 3,966,773 and 3,952,033. ##STR36##

In accordance with the scheme as outlined hereinabove in Flowsheet Gwherein R₃ is triloweralkylsilyl, tetrahydropyranyl or triphenylmethyl,R₁ ' is C₁ -C₆ alkoxy, tetrahydropyranyloxy, triloweralkylsilyloxy, ortriphenylmethoxy and R₄ and R₁ are hereinabove defined, thecyclopentenones Ia or Ib are treated with 1-equivalent of2-mercoptoethanol in the presence of sodium methoxide and methanol forbetween 1-5 hours at room temperature affording the4-(2-hydroxyethylthio)-cyclopentenones (II), which are converted intotheir trimethylsilyl, tetrahydropyranyl or triphenylmethyl ether esters(III) in the usual manner.

The preparation of the prostaglandin congeners of this invention aredescribed in Flowsheet H wherein R' is selected from the groupconsisting of: ##STR37## wherein R₅, R₆, R₇, R₈, R₁₀, R₁₁, and R₁₂ areas hereinabove defined, and p is 1 or 2.

In accordance with Flowsheet H, as suitably protected vinyliodide (65)is treated with either one equivalent of n-butyllithium or 2 equivalentsof t-butyllithium at low temperature, preferably -30° to -78° C. in aninert solvent, eg. hexane, ether or toluene to provide thetrans-alkenyl-lithium reagent (67).

Alternatively, the vinyllithium reagent (67) can be prepared bytreatment of a vinylstannyl derivative such as (66) with n-butyllithiumat -10° to -78° C.

For the preparation of the asymmetrical lithio cuprate (68) or the like,a solution of one molar equivalent of copper (I)-1-alkyne, preferablecopper (I)-1-pentyne in anhydrous tributyl phosphine, preferably one tofive molar equivalents, and anhydrous ether is added to one molarequivalent of the aforementioned vinyllithium solution cooled to about-79° C. After about one hour at this temperature, a molar equivalent ofthe requisite cyclopentenone (71) is added. After several hours at -30°C. to -70° C. the reaction mixture is quenched with aqueous ammoniumchloride solution and the blocked product (72) is isolated in the usualmanner.

It is also possible to effect conjugate 1,4-addition with theasymmetrical lithio cuprate (70) derived from vinyllithium (67) andcuprous throphenoxide. A solution of vinyllithium (67) in ether at -78°C. is reacted with an equimolar amount of a reagent prepared byadmixture in ether at a temperature of 0° C. to -78° C., of equimolaramounts of cuprous thiophenoxide and copper (I) iodidetributylphosphonium complex. After about 30 minutes at this temperature,the lithio cuprate (70) is treated with the requisite cyclopentenone(71) as described hereinabove for the conjugate addition with 1-alkynyllithio cuprate (68).

For the preparation of the symmetrical lithio cuprate (69) one molarequivalent of copper (I) iodide tributylphosphine complex, dissolved inanhydrous ether, is added at about -78° C. to two molar equivalents ofthe aforementioned vinyl iodide (65) solution in hexanes, cooled to -78°C. After about one hour at this temperature, the lithio cuprate (69) istreated with the requisite cyclopentenone (71) as described hereinabove,for the conjugate addition with the 1-alkynl lithio cuprate (68).

The procedures for conjugate addition involving organocopper reagentsare well known in the art, see for example, C. J. Sih, et. al., J. A. C.S., 97, 865 (1975).

In the cases where R'₁ ═trimethylsilyloxy in cyclopentenone (71) theconjugate addition is performed at -78° C. to -40° C. The reaction isquenched by addition of an ether solution of acetic acid. Removal ofblocking groups is then carried out as described in the reference aboveto provide the product (73) wherein R₁ and R are hereinabove described.

All available evidence leads us to believe that the β-chain introducedby the cuprate process occupies a position trans to the 11-oxy function.Similarly, we are fed to the conclusion that in the product (73) the twoside-chains attached to C₈ and C₁₂ are trans to each other. However, weare not certain of this configurational relationship in the product asit is obtained directly from the cuprate process. These products mayhave the side-chain in a trans or cis-relationship or they may be amixture containing both the trans- and cis-isomers. This is indicated inthe nomenclature of the compounds involved by the designation 8ε. Inorder to ensure a trans-relationship in (73) these products can besubmitted to conditions known in the literature to equilibrate thecis-8-iso-PGE₁ to a mixture containing about 90% of the trans product.These conditions involve treatment with potassium acetate in aqueousmethanol for 96 hours at room temperature. ##STR38##

The 9-keto derivatives of this invention can be converted to thecorresponding 9-hydroxy derivatives as described in Flowsheet I. If thisconversion is effected with sodium borohydride, the product is a mixtureof 9α- and 9β-hydroxy derivatives (75) and (76) respectively, as setforth in the following reaction scheme, wherein R₁, R and Z are ashereinabove defined. ##STR39##

When the reaction is carried out with lithium perhydro-9b-boraphenylylhydride [H. C. Brown and W. C. Dickason, J.A.C.S., 92, 709 (1970)] orlithium tris-(t-butyl)-borohydride [H. C. Brown and S. Krishnamurthy,ibid., 94, 7159 (1972)] the product is at least predominantly the9α-hydroxy derivative wherein the 9-hydroxy group is cis to the sidechain attached to C8 and to the 11-mercapto function. In accordance withaccepted convention, an α-substituent at the 8-, 9-, 11- or 12-positionsis behind the plane of the paper, whereas a β-substituent at thesepositions is in front of the plane of paper. This is usually representedby a--bond for an α-substituent, a bond for a β-substituent, and a bondwhere both are indicated.

The carboxylic acids of this invention can be readily converted to thevarious alkyl esters of this invention by treatment in the usual mannerwith the appropriate diazoalkane. The preparation of diazoalkanes byvarious procedures are well described in the art. See for example C. D.Gutsche, Organic Reactions, 8, 389 (1954). Certain of the esters of thisinvention can also be obtained directly by use of the appropriatecyclopentenone ester. The various esters can also be prepared by any ofseveral procedures well-known in the art via an acid chloride (priorblocking of free alcohol groups with appropriate blocking groups such astrialkylsilyl, tetrahydropyranyl and the like) or mixed anhydrides andtreatment of these intermediates with the appropriate alcohol. Mixedanhydrides can be obtained by treatment of the prostaglandin acid in asolvent such as dioxane at a temperature in the range of 0° C. to 15° C.with a molar equivalent of a tri-alkylamine, preferably triethylamine,tributylamine and the like, and then a molar equivalent of isobutylchlorocarbonate or the like. The resulting mixed anhydrides is thentreated with the appropriate alcohol to give the derivative product.[For a pertinent literature analogy see Prostaglandins, 4, 738 (1973).]

An alternative procedure involves treatment of the prostaglandin acidwith a molar equivalent of the trialkyl amine in an excess of theappropriate alcohol in an anhydrous solvent such as methylene chloride,a molar equivalent of p-toluenesulfonyl chloride is then added (ifnecessary, a second molar equivalent can be added) and after stirring atambient temperatures for about 15 minutes to one hour the product isworked-up in the usual manner. (For a pertinent literature analogy, seeU.S. Pat. No. 3,821,279.) A third procedure involves the use ofdicyclohexylcarbodiimide in the usual manner; for a pertinent literatureanalogy see German Offen. 2,365,205; Chem. Abst., 81, 120098g (1974).

The esterified alcohol derivatives of this invention are also preparedin the usual manner by procedures well known in the art from theappropriate alkanoic acid anhydride or acid chloride.

When the compounds of this invention are prepared from racemic startingcompounds, two racemates are obtained. In appropriate instances theseracemates may be separated from each other by careful application of theusual chromatographic procedures. In the more difficult instances it maybe necessary to apply high pressure liquid chromatography includingrecycling techniques. [See G. Fallick, American Laboratory, 19-27(August 1973) as well as references cited therein. Additionalinformation concerning high speed liquid chromatography and theinstruments necessary for its application is available from WaterAssociate Inc., Maple Street, Mildord, Mass.]

In addition, optically active congeners can be prepared by treating aracemic mixture of a cyclopentenone (71) with the cuprate derived froman optically active vinyliodide such as (77) to give two diasteriomers(78) and (79) as shown in Flowsheet J. Chromatographic separation by theusual methods, after removal of the protecting groups, will then provideboth the nat (78) and ent (79) epimers possessing the same absoluteconfiguration at the carbon bearing the hydroxyl vinyl cuprateprecursor.

Methods for the resolution of the vinyliodides or precursors to thevinyliodides such as propargylic or homopropargylic alcohols are knownin the art. [J. Fried, et. al., Annals. New York Academy of Science,180, 60 (1971); R. Pappo, et.al., Ibid, 180, 66 (1970); A. F. Kluge, et.al., J.A.C.S., 94, 7827 (1972); U.S. Pat. No. 3,950,446]. ##STR40##

EXAMPLE 1 Preparation of ethyl 2,2-trimethylenehexanoate

To a stirred solution of 27.6 g of freshly distilledN-isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran cooled to-78° C. is added at a fast rate 96 ml of 2.04 M n-butyllithium inhexane. To the resulting solution is added dropwise 25 g of ethylcyclobutanecarboxylate. After 30 minutes the resulting solution isallowed to warm to ambient temperature, is transferred to a droppingfunnel under nitrogen and is added dropwise over a period of 11/4 hoursto a solution of 54 g of n-butyl iodide in 100 ml of drydimethylsulfoxide maintaining the temperature at 16°-20° C. Stirring iscontinued for an additional 30 minutes. The separated salts are removedby filtration, the mother liquor is taken to a small volume and theresulting oil is diluted with hexanes. This solution is washed with 2%hydrochloric acid, saturated sodium chloride solution, and dried withanhydrous magnesium sulfate. The solvent is removed and the residual oilis distilled to give 14.6 g (41 %) of product, bp 84°-87° C. (10 mm).

EXAMPLE 2 Preparation of ethyl 2,2-tetramethylenehexanoate

In the manner described in Example 1, treatment of the lithium salt ofethyl cyclopentanecarboxylate with n-butyl iodide furnishes the subjectproduct.

EXAMPLE 3 Preparation of 2,2-trimethylenehexan-1-ol

To a stirred solution of 20 g of ethyl 2,2-trimethylenehexanoate(Example 1) in 100 ml of dry toluene, in an argon atmosphere and cooledin an ice bath, is added dropwise 250 ml (2 molar equivalents) of 0.89 Mdiisobutylaluminum hydride in toluene. The resulting solution is stirredat ambient temperature for 2 hours and then poured into excess iced 5%hydrochloric acid. The organic phase is separated and washed with 5%hydrochloric acid, saturated sodium chloride solution, dried withanhydrous magnesium sulfate and taken to dryness to give 14.8 g (96%) ofoil; bp 92°-93° C. (10 mm).

EXAMPLE 4 Preparation of 2,2-tetramethylenehexan-1-ol

In the manner described in Example 3, treatment of ethyl2,2-tetramethylenehexanoate (Example 2) with 0.89 molardiisobutylaluminum hydride furnishes the subject product.

EXAMPLE 5 Preparation of 2,2-trimethylenehexaldehyde

Chromium trioxide (61.5 g), dried in a vacuum desiccator overphosphorous pentoxide, is added to an ice cold solution of 97 g of drypyridine in one liter of dry methylene chloride. The deep red suspensionis stirred for 15 minutes at 0° C. and then for 45 minutes at ambienttemperature. A solution of 14.5 g of 2,2-trimethylenehexanol-1 (Example3) in 55 ml of methylene chloride is added all at once to thesuspension. A black tarry deposit is formed immediately. After stirringat ambient temperature for 15 minutes the solution is decanted from thetarry deposit which is then triturated four times with small portions ofmethylene chloride. The combined extracts are washed twice with ice cold5% sodium hydroxide, ice cold 5% hydrochloric acid and finally withsaturated sodium chloride solution, dried with magnesium sulfate andtaken to dryness. Distillation gives 12.9 g of product; bp 69° C. (11mm).

EXAMPLE 6 Preparation of 2,2-tetramethylenehexaldehyde

Oxidation of 2,2-tetramethylenehexan-1-ol (Example 4) with chromiumtrioxide-pyridine complex in the manner described in Example 5 furnishesthe subject product.

EXAMPLE 7 Preparation of 4,4-trimethylene-1-octyn-3-ol

To a solution of lithium acetylide-ethylenediamine complex (9.4 g) in 90ml of dry dimethylsulfoxide, cooled in an ice bath, is added 12.94 g of2,2-trimethylenehexaldehyde (Example 5) in 10 ml of dimethylsulfoxidedropwise, at such a rate that the temperature is maintained at 20°-25°C. The solution is stirred at ambient temperature for 12 hours and thenpoured into a mixture of ice cold 2% hydrochloric acid and ether. Theether layer is separated and the aqueous phase is extracted with ether.The combined ether extracts are washed with saturated sodium chloridesolution, dried with anhydrous magnesium sulfate and taken to dryness.Distillation provides 13.53 g of product; bp 108°-109° C. (13 mm).

EXAMPLE 8 Preparation of 4,4-tetramethylene-1-octyn-3ol

Treatment of 2,2-tetramethylenehexaldehyde (Example 6) with lithiumacetylide-ethylenediamine complex in dimethylsulfoxide in the mannerdescribed in Example 4 is productive of the subject compound.

EXAMPLE 9 Preparation of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne

To a stirred solution of 5.3 g of 4,4-trimethylene-1-octyn-3-ol (Example7) and 5.42 g of imidazole in 32 ml of dry dimethylformamide, cooled inan ice bath under argon atmosphere is added 4.35 g ofchlorotrimethylsilane. After stirring at 0° C. for 15 minutes, thesolution is stirred at ambient temperature for 18 hours and the pouredinto 200 ml of hexanes. The solution is washed twice with ice coldwater, saturated sodium chloride solution, dried with anhydrousmagnesium sulfate and taken to dryness. Distillation furnishes 6.02 g(80%) of colorless oil; bp 110°-112° C. (14 mm).

EXAMPLE 10 Preparation of4,4-tetramethylene-3-trimethylsilyloxy-1-octyne

Treatment of 4,4-tetramethylene-1-octyn-3-ol (Example 8) withchlorotrimethylsilane in dimethylformamide containing imidazole asdescribed in Example 5 furnishes the subject product.

EXAMPLE 11 Preparation of1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne

To a solution of 25 g of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne(Example 9), stirred under argon atmosphere at -78° C., is addeddropwise 93 ml of 2.3 M n-butyllithium in hexane at a rate to maintainthe temperature below -40° C. After stirring for 40 minutes, a solutionof iodine is allowed to warm to ambient temperature and 10% aqueoussodium thiosulfate solution is added until the purple color is removed.The organic phase is washed with dilute aqueous sodium thiosulfatesolution, saturated sodium chloride solution, dried with anhydroussodium sulfate and taken to dryness to afford the subject product as anoil.

EXAMPLE 12 Preparation of1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-cis-octene

To a solution of 30 g of1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 10) in 100ml of methanol, under argon atmosphere is added 54 g of potassiumazodicarboxylate [J. Thiele, Annalen der Chemie, 271, 127 (1892)]. Tothis solution is added dropwise 45 ml of acetic acid over a period ofabout 2 hours. The solids are removed by filtration and the motherliquor is reduced to a small volume, diluted with water and extractedwith ether. The ether is evaporated and the residual oil is stirred with250 ml of 1 M sodium bicarbonate solution. The solution is extractedseveral times with ether and the combined extracts are washed withsaturated sodium chloride solution, dried with anhydrous sodium sulfateand taken to dryness to furnish the subject product as an oil.

EXAMPLE 13 Preparation of1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-trans-octene

To a mixture of 4.76 g of sodiumborohydride and 23.6 g of2-methyl-2-butene in 220 ml of dry tetrahydrofuran at -5° C. is addeddropwise 23.8 g of freshly distilled borontrifluoride etherate. Theresulting mixture is stirred at -5° C. to -0° C. for 2 hours and to itis added dropwise a solution of 20 g of4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 12) in 20 ml ofdry tetrahydrofuran. The resulting mixture is stirred at ambienttemperature for 21/2 hours. The mixture is then cooled to -5° C. andthere is added 44 g of trimethylene oxide protionwise over a period of20 minutes, maintaining the temperature at 15°-20° C. The mixture isstirred at ambient temperature for 2 hours and then pouredsimultaneously, with a solution of 119 g of iodide in 290 ml oftetrahydrofuran, into 1490 ml of 15% aqueous sodium hydroxide solution.After stirring for 30 minutes the organic phase is separated and heaqueous phase is extracted with ether. The combined organic phase iswashed with 5% aqueous sodium thiosulfate solution, saturated sodiumchloride solution, dried with anhydrous magnesium sulfate and taken todryness to give 27 g of oily material. Chromatography on 135 g offlorisil and eluting with 500 ml of hexanes furnishes 24 g of oilyproduct which is shown to be contaminated with starting material andiodoform by infrared and thin layer chromatography. The material ispurified by removing the trimethylsilyl group in the following manner.The crude product is dissolved in 350 ml of aceticacid-tetrahydrofuran-water (4:2:1) by stirring at ambient temperaturefor 5 minutes. The solvent is removed under reduced pressure and theresidual oil containing mainly1-iodo-3-hydroxy-4,4-trimethylene-1-trans-octene is applied to a 2"(flat) dry column containing 1200 g of Woelm silica gel. The column isdeveloped with benzene, cut into one-inch segments and each segment iseluted with chloroform. Combination of the appropriate fractions affords300 mg of iodomethane, 2.8 g of 4,4-trimethylene-1-octyne-3-ol, and 11.6g of 1-iodo-3-hydroxy-4,4-trimethylene-1-trans-octene. Silylation ofthis material in the manner described above followed by distillation ofthe residual oil furnishes 13 g of pure product; bp 83°-84° C. (0.2 mm).

EXAMPLE 14 Preparation of1-iodo-4,4-tetramethylene-3-trimethylsilyloxy-1-trans-octene

Treatment of 4-tetramethylene-3-trimethylsilyloxy-1-octyne (Example 10)in the manner described in Example 13 furnishes the subject product.

EXAMPLES 15-20

Treatment of the lithium salt of ethyl cyclobutanecarboxylate with thealkyl halides listed in Table 1 below by the procedure described inExample 1 furnishes the 2,2-trimethylene esters of the table.

                  TABLE 1                                                         ______________________________________                                        Ex.  Alkyl Halides                                                                               Product 2,2-Trimethylene esters                            ______________________________________                                        15   propyl iodide                                                                              ethyl 2,2-trimethylenepentanoate                            16   amyl iodide  ethyl 2,2-trimethyleneheptanoate                            17   hexyl iodide ethyl 2,2-trimethyleneoctanoate                             18   benzyl iodide                                                                              ethyl 2,2-trimethylene-                                                       3-phenylpropionate                                          19   2-cyclopentyl-1-                                                                           ethyl 2,2-trimethylene-                                          ethyl bromide                                                                              4-cyclopentylbutyrate                                       20   1-chloro-2-butyne                                                                          ethyl 2,2-trimethylene-4-hexynoate                          ______________________________________                                    

EXAMPLES 21-27

Reduction of the various esters listed in Table 2 below withdiisobutylaluminum hydride all in the manner described in Example 3above is productive of the alcohols of the table.

                  TABLE 2                                                         ______________________________________                                             Starting Esters                                                          Ex.  of Example   Product Alcohols                                            ______________________________________                                        21   15          2,2-trimethylenepentan-1-ol                                  22   16          2,2-trimethyleneheptan-1-ol                                  23   17          2,2-trimethyleneoctan-1-ol                                   24   18          2,2-trimethylene-3-phenylpropan-1-ol                         25   19          2,2-trimethylene-4-cyclopentylbutan-1-ol                     26   20          2,2-trimethylene-4-hexyn-1-ol                                27   55          2,2-trimethylene-4-cis-hexen-1-ol                            ______________________________________                                    

EXAMPLES 28-34

Oxidation of the alcohols listed in Table 3 below with chromiumtrioxide-pyridine complex by the procedure described in Example 5 abovefurnishes the corresponding aldehydes of the table.

EXAMPLES 28-34

Oxidation of the alcohols listed in Table 3 below with chromiumtrioxide-pyridine complex by the procedure described in Example 5 abovefurnishes the corresponding aldehydes of the table.

                  TABLE 3                                                         ______________________________________                                             Starting Alcohols                                                        Ex.  of Example    Product 2,2-Trimethylenealdehydes                          ______________________________________                                        28   21           2,2-trimethylenevaleraldehyde                               29   22           2,2-trimethyleneheptaldehyde                                30   23           2,2-trimethyleneoctaldehyde                                 31   24           2,2-trimethylene-3-                                                           phenylpropionylaldehyde                                     32   25           2,2-trimethylene-4-                                                           cyclopentylbutyraldehyde                                    33   26           2,2-trimethylenehex-4-yn-1-al                               34   27           2,2-trimethylene-4-cis-hexene-1-al                          ______________________________________                                    

EXAMPLES 35-41

Treatment of the various aldehydes listed below in Table 4 with lithiumacetylide-ethylenediamine complex in the manner described in Example 7furnishes the hydroxyacetylenes of the table.

                  TABLE 4                                                         ______________________________________                                             Starting Aldehydes                                                       Ex.  of Example     Product Hydroxyacetylenes                                 ______________________________________                                        35   28            4,4-trimethylene-1-heptyn-3-ol                             36   29            4,4-trimethylene-1-nonyn-3-ol                              37   30            4,4-trimethylene-1-decyn-3-ol                              38   31            4,4-trimethylene-5-phenyl                                  1-pentyn-3-ol                                                                 39   32            4,4-trimethylene-6-cyclopentyl                             1-hexyn-3-ol                                                                  40   33            4,4-trimethylene-1,6-octadiyn-3-ol                         41   34            4,4-trimethylene-4-cis-hexene-3-ol                         ______________________________________                                    

EXAMPLES 42-48

Treatment of the various alcohols listed below in Table 5 withchlorotrimethylsilane in the manner described in Example 9 furnishes thecorresponding trimethylsilyloxy acetylenes of the table.

                  TABLE 5                                                         ______________________________________                                             Starting Alcohols                                                        Ex.  of Example    Product Trimethylsilyloxyacetylenes                        ______________________________________                                        42   35           4,4-trimethylene-3-trimethylsilyloxy-                                         1-heptyne                                                   43   36           4,4-trimethylene-3-trimethylsilyloxy-                                         1-nonyne                                                    44   37           4,4-trimethylene-3-trimethylsilyloxy-                                         1-decyne                                                    45   38           4,4-trimethylene-3-trimethylsilyloxy-                                         5-phenyl-1-pentyne                                          46   39           4,4-trimethylene-3-trimethylsilyloxy-                                         6-cyclo-pentyl-1-hexyne                                     47   40           4,4-trimethylene-3-trimethylsilyloxy                                          1,6-octadiyne                                               48   41           4,4-trimethylene-3-trimethylsilyloxy-                                         4-cis-octene-1-yne                                          ______________________________________                                    

EXAMPLES 49-54

In the manner described in Example 13 treatment of the variousacetylenes of Table 6 below with disiamylborane, made in situ fromsodium borohydride and 2-methyl-2-butene, followed by oxidation of theso formed organoborane with trimethylamine oxide followed by treatmentof this product with iodine and sodium hydroxide furnishes thetrimethylsilyliodovinylcarbinols of the table.

                                      TABLE 6                                     __________________________________________________________________________         Starting Acetylenes                                                      Example                                                                            of Example                                                                               Product Trimethylsilylvinylcarbinols                          __________________________________________________________________________    49   42        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                trans-heptene                                                  50   43        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                trans-nonene                                                   51   44        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                trans-decene                                                   52   45        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-5-                                phenyl-1-trans-pentene                                         53   46        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-6-                                cyclopentyl-1-trans-hexene                                     54   47        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                trans-octen-6-yne                                              __________________________________________________________________________

EXAMPLE 55 Preparation of ethyl 2,2-trimethylene-4-cis-hexenoate

A solution of 5 g of ethyl 2,2-trimethylene-4-hexynoate (Example 20) in40 ml of dry pyridine is hydrogenated in a Parr apparatus using 600 mgof 5% palladium on barium sulfate. After one hour when hydrogen uptakeis complete, the solution is filtered through celite and the motherliquor is taken to dryness to furnish 4 g of product as an oil.

EXAMPLE 56 Preparation of 3-tetrahydropyranyloxy-1-propyne

To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-1-propyne and 260g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooledto 0° C. in an ice bath, is added a solution of 20 mg ofpara-toluenesulfonic acid in 100 ml of methylene chloride, dropwise. Thereaction mixture is stirred at 0° C. for one-half hour, and at ambienttemperature for one hour. It is then poured into 200 ml of a 5% solutionof sodium bicarbonate, the organic phase is separated, the aqueous phaseextracted with 100 ml of methylene chloride, the combined organic phaseswashed with 100 ml of a solution of brine, dried over sodium sulfate,and evaporated under vacuum (12 mm) at 45° C. to give 300 g of crudeproduct, which is purified by fractional distillation, bp 71°-73° C. (14mm) to yield 250 g (89%) of a liguid.

EXAMPLE 57 Preparation of3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne

To a stirred -20° C. solution of 125 g (0.89 mol.) of3-tetrahydropyranyloxy-1-propyne (Example 56) in 450 ml of ether, undera nitrogen atmosphere, is added dropwise, over one hour, a solution of45 ml (0.89 mol.) of 2.0 N n-butyllithium in hexane. After 150 ml of dryether is added and the mixture stirred at -20° C. for 30 minutes, asolution of 98 g (0.89 mol.) of trimethylchlorosilane in 73 ml of etheris added dropwise. Stirring is continued for 30 minutes at -20° C. andat ambient temperature for 18 hours. The reaction mixture is againcooled to -20° C., and a solution of 90 ml of acetic acid in 300 ml ofether is added dropwise, followed by 90 ml of water. It is then dilutedwith 500 ml of water, and extracted 3 times with 300 ml of 5% sodiumbicarbonate solution. The organic phase is separated, washed with 500 mlof a saturated brine solution, dried over sodium sulfate, and evaporatedat 40° C. under vacuum (12 mm.). The curde product is fractionallydistilled, bp 120°-125° C. (18 mm.), to yield 120 g of an oil.

EXAMPLE 58 Preparation ofd,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne

To a stirred -78° C. solution of 62 ml (124 mmol.) of a 2.0 M solutionof n-butyllithium in hexane and 50 ml of dry tetrahydrofuran, under anitrogen atmosphere is added dropwise, a solution of 24 g (113 mmol.) of3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne (Example 57) in 35 mlof tetrahydrofuran. This red solution is stirred one hour at -78° C.,then a freshly prepared solution of zinc iodide (135 mmol.) in 125 ml oftetrahydrofuran [F. Mercier, R. Epsztein, and S. Holand, Bull. Soc.Chim. France, 2, 690 (1972)] is added dropwise at -78° C. until themixture turns yellow. After stirring an additional hour at -78° C., asolution of 21 g (250 mmol.) of n-valeraldehyde in 35 ml oftetrahydrofuran is added dropwise and the reaction mixture stirred forone hour at -78° C. and 18 hours at ambient temperature. It is thencooled to 0° C. and a solution of 12 ml of acetic acid in 65 ml of etheris added dropwise, followed by 75 ml of ice-water. The phases areseparated and the aqueous phase is extracted twice with ether. Thecombined organic phases are washed 3 times with saturated sodiumbicarbonate solution, until the last wash is basic, then with asaturated brine solution, dried over sodium sulfate, and evaporated togive 40 g of yellow oil. The crude product may be purified on a 4"×40"dry column of alumina, and eluted with chloroform.

I.r.: neat; 3550 (OH), 2200 (C.tbd.C), 840,750 [(CH₃)₃ Si], cm⁻¹.

EXAMPLE 59 Preparation ofd,l-erythro-3,4-dihydroxy-1-trimethylsilyl-1-octyne

A solution of 19.6 g (0.066 mol) ofd,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne(Example 58) in 55.5 ml of ethanol, 22.2 ml of acetic acid, and 22.2 mlof water is heated at reflux for 3 hours. The cooled mixture is taken todryness and evaporated twice with benzzene. The residue is taken up inhexane, washed 3 times with saturated potassium bicarbonate solution,dried with magnesium sulfate, and evaporated-to give 17.0 g of crudeproduct.

Ir: neat, 3500-3400, broad (two OH).

EXAMPLE 60 Preparation ofd,l-erythro-3,4-isopropylidenedioxy-1-trimethylsilyll-1-octyne

To a stirred solution of 17.0 g (79.5 mmol.) of cruded,l-erythro-15,16-dihydroxy-1-trimethylsilyl-1-octyne (Example 59) is33.6 ml of 2,2-dimethoxy propane at 0° C., is added 0.05 ml of 60%perchloric acid. After 30 minutes at ambient temperature, the mixture isshaken with 50 ml of hexane and 25 ml of saturated sodium bicarbonatesolution. The hexane phase is separated, dried with magnesium sulfate,and evaporated to give 19.0 g of crude product.

EXAMPLE 61 Preparation of d,l-erythro-3,4-isopropylidenedioxy-1-octyne

A mixture of 19.0 g (75.0 mmol.) of cruded,l-erythro-3,4-isopropylidenedioxy-1-trimethylsilyl-1-octyne (Example60) with 95 ml of methanol and 3.0 g of potassium carbonate is refluxedfor one hour. The mixture is cooled and evaporated at 50° C. (13 mm),taken up in 250 ml of benzene, and washed with 100 ml of water. Thewater is saturated with salt, the organic phase separated, dried withmagnesium sulfate, and evaporated to give 12 g of crude product.Fractional distillation yields 7.0 g of the subject compound as acolorless oil, bp 103°-106° C. (13 mm).

Ir: neat; 3300 sharp (H--C.tbd.C), 2100, (C.tbd.C), 780 (erythroconfiguration) cm⁻¹.

nmr: δ_(TMS) ^(CDCl).sbsp.3 ; 4.75 (dd., 1, C.tbd.C--CH--CH, J=2 Hz, J=5Hz), 4.10 (m, 1, C.tbd.C--CH--CH--CH₂, 2.5 (d, 1, H--C C--CH), 1.9-1.2(m, 14, alkyl), 0.90 (m, 3H, CH₂ CH₃).

EXAMPLE 62 Preparation ofd,l-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-octene

To a stirred 0° C. slurry of 0.852 g (0.023 mol.) of sodium borohydrideand 4.21 g (0.060 mol.) of 2-methyl-2-butene in 40 ml of drytetrahydrofuran, under an argon atmosphere, is added dropwise 4.26 g(0.030 mol.) of boron trifluoride etherate complex. A solution of 2.73 g(0.015 mol.) of d,l-erythro-3,4-isopropylidenedioxy-1-octyne (Example61) in 5 ml of tetrahydrofuran is added dropwise, the ice bath removed,and the mixture allowed to stir at ambient temperature for two hours. Itis then cooled again to 0° C., and 2.88 g (0.105 mol.) of drytrimethylamine oxide is added in portions over 30 minutes. Afterstirring 3 hours at room temperature, this mixture is pouredsimultaneously with a 0° C. solution of 2.13 g of iodine in 53 ml oftetrahydrofuran into 766 ml of a 0° C. 15% solution of sodium hydroxidein water and the whole stirred vigorously at 0° C. for 45 minutes. Theorganic phase is separated, the aqueous phase is extracted twice withether, the combined organic phases are washed with a 5% solution ofsodium thiosulfate, dried with magnesium sulfate, and evaporated. Thecrude product is chromatographed o dry column of silica gel, by elutingwith chloroform, to yield 1.2 g (25%) of a yellow oil.

Ir: neat; 1599 sharp, 945 ##STR41##

EXAMPLE 63 Preparation ofd,l-erythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A solution of 3.0 g (13.2 mmol.) ofd,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyneis heated at 100° C. for 15 hours with 3 ml of acetic anhydride and 10ml of pyridine. The mixture is evaporated to dryness, dissolved inether, washed with sodium bicarbonate solution and water. The organicphase is dried over magnesium sulfate and evaporated to give 2.5 g ofthe subject compound as an oil.

Ir: neat; 2200 (C C), 1730 (C═O), 830, 760 [(CH₃)₃ Si], cm⁻¹.

EXAMPLE 64 Preparation ofd,l-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

In the manner of Example 59, 2.5 g (7.4 mmol.) ofd,l-erythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne(Example 63) in a solution of ethanol, acetic acid, and water is heatedat 100° C. for 3 hours. A ter workup, the crude product ischromatographed on a 7/8"×22" dry column of silica gel, and eluted withchloroform to give 1.0 g of a yellow oil.

Ir: neat; 3500 (OH), 1730 (C═O) cm⁻¹.

EXAMPLE 65 Preparation ofd,l-erythro-3-paratoluenesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

To a solution of 7.5 g (41.0 mmol.) ofd,l-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 64)in 41 ml of dry pyridine is added 11.0 g (58 mmol.) ofpara-toluenesulfonyl chloride and the resulting solution is stirred at25° C. for 15 hours. The mixture is then warmed at 40° C. for one hour,and after cooling, partitioned between 500 ml of diethyl ether and 100ml of 1.0 N hydrochloric acid. The organic phase is washed three timeswith 100 of 1.0 N hydrochloric acid, once with dilute sodium bicarbonatesolution, dried over magnesium sulfate, and evaporated under reducedpressure to give an oil. The crude product is purified on a 2"×24" drycolumn of silica gel, and eluted with chloroform to yield a yellow oil.

Ir: neat; 1730 (C═O), 1595 (aromatic) cm⁻¹.

EXAMPLE 66 Preparation ofd,l-threo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A mixture of 15.5 g (39.0 mmol.) ofd,l-erythro-3-para-toluennesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne(Example 65), 5.0 g of calcium carbonate, 25 ml of water and 250 ml oftetrahydrofuran is refluxed with stirring for 4 days. The mixture iscooled, 100 ml of water added and the organic phase separated. Theaqueous phase is extracted with ether, the combined organic phases driedwith magnesium sulfate, and evaporated. The crude product ischromatographed on a 3"×30" dry column of silica gel, and eluted withchloroform to give 7.0 g of an oil.

Ir: neat; 3500, (OH), cm⁻¹.

EXAMPLE 67 Preparation of d,l-threo-3,4-dihydroxy-1-octyne

A solution of 7.0 g (28 mmol.) ofd,l-threo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 66)in 50 ml of methanol is stirred at room temperature for 24 hours with asolution of 6.3 g (112 mmol.) of potassium hydroxide in 50 ml of water.The mixture is extracted twice with hexane, washed with 0.5 Mhydrochloric acid, brine, and dried with magnesium sulfate. Afterevaporation, the subject compound is obtained as a yellow oil.

Ir: neat, 2500 broad (2-OH), cm⁻¹.

EXAMPLE 68 Preparation of d,l-threo-3,4-isopropylidenedioxy-1-octyne

In the manner of Example 60, treatment of a solution ofd,l-threo-3,4-dihydroxy-1-octyne (Example 67) in dimethoxypropane with60% perchloric acid, and fractional distillation (12 mm) is productiveof the subject compound as a colorless oil, containing 15% ofd,l-erythro-3,4-isopropylidenedioxy-1-octyne (Example 60), as animpurity.

Ir: neat; 810 (threo configuration).

nmr: δ_(TMS) ^(CDCl).sbsp.3 ; 4.2 (dd, 1, --C.tbd.C--CH--, J's - 2H_(z), 6 H_(z)), 4.1-3.9 (m, 1, --C.tbd.C--CH--CH--CH₂ --), 2.5 (d, 1,H--C.tbd.C--, J=2 H_(z)), 1.9-1.2 (m, 14, alkyl), 0.90 (m, 3H, CH₂--CH₃).

EXAMPLE 69 Preparation ofd,l-threo-1-iodo-3,4-isopropylidenedioxy-trans-1-octene

In the manner of Example 62,d,l-threo-3,4-isopropylidenedioxy-trans-1-octyne (Example 68) is treatedsuccesively with disiamylborane, trimethylamine oxide, iodine, andsodium hydroxide to give the subject compound.

EXAMPLE 70 Preparation ofd,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne

Alkaline hydrolysis ofd,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne(Example 58) by the procedure of Example 61 is productive of the subjectcompound.

EXAMPLE 71 Preparation ofd,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne

To a stirred slurry of 6.0 g (150 mmol.) of a 60% oil dispersion ofsodium hydride and 96 g of iodomethane, under an argon atmosphere, isadded 700 ml of dry tetrahydrofuran. The stirred mixture is cooled to-20° C. and a solution of 30 g (133 mmol.) ofd,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne (Example 70), isadded dropwise, followed by 0.1 ml of methanol. The mixture is stirredat ambient temperature for 24 hours, 10 ml of methanol is added, andevaporated. The residue is taken up in ether, washed 3 times with water,dried over magnesium sulfate, and evaporated. The crude product ispurified by fractional distillation to yield 16.3 g of a colorless oil,bp 137°-140° C. (12 mm).

EXAMPLE 72 Preparation ofd,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-1-octen

In the manner of Example 62, 1.20 g (5.0 mmol.) ofd,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne (Example 71) istreated successively with disiamylborane, trimethylamine oxide, iodine,and sodium hydroxide. Chromatography on a 2"×36" dry column of silicagel and elution with chloroform is productive of 0.80 g (40%) of thesubject compound as an oil.

nmr: δ_(TMS) ^(CDCl).sbsp.3 ; 7.9-6.1 (m, 2, HC═CH), 4.9-4.6 (2 m, 2,c═C--CH, O--CH--O), 4.3-4.0 (m, 1, c═c--CH--CH--CH₂), 3.9-3.0 (m, 6, CH₂--O--CH, OCH₃), 1.8-1.2 (m, 12H, alkyl), 0.9 (m, 3, --CH₃).

EXAMPLE 73 Preparation ofd,l-erythro-3-hydroxy-4-methoxy-1-iodo-trans-1-octene

A solution of 3.10 g (8.24 mmol.) ofd,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-1-octene(Example 72) in 60 ml of acetic acid, 30 ml of tetrahydrofuran, and 15ml of water is stirred at ambient temperature for 18 hours. It is thenevaporated at 70° C. under high vacuum (1.0 mm), and three times with 40ml of toluene to give the crude product as an oil.

EXAMPLE 74 Preparation ofd,l-erythro-3-trimethylsilyloxy-4-methoxy-1-iodo-trans-1-octene

To a stirred solution of 3.0 g (10.2 mmol.) ofd,1-erythro-3-hyroxy-4-methoxy-1-iodo-trans-1-octene (Example 73) in11.0 ml of dry dimethylformamide and 1.90 g (28.0 mmol.) of imidazolecooled to 0° C. is added, dropwise, 1.35 g (12.5 mmol.) oftrimethylsilyl chloride. The reaction mixture is stirred a further 4hours at room temperature. It is then poured into a mixture of 100 ml ofhexane and 25 ml of water, the organic phase is separated, washed twicewith water, once with a solution of saturated sodium chloride, driedover magnesium sulfate, and evaporated. The crude product is purified byfractional distillation to yield 2.0 g of a colorless oil, bp 82°-83° C.(0.3 mm).

Ir: neat, 1602 sharp ##STR42## 840, 750 broad [(CH₃)₃ Si-], cm⁻¹.

EXAMPLE 75 Preparation ofd,l-erythro-1-iodo-3,4-dihydroxy-trans-1-octene

A solution of 1.40 g (4.50 mmol.) ofd,l-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-octene (Example 62)in 30 ml of acetic acid, 10 ml of tetrahydrofuran and 10 ml of water isstirred and heated at 50° C. for five hours. It is then evaporated at40° C. under high vacuum (1.0 mm), and twice more with 50 ml of benzene.Crystallization from 10 ml of chloroform at 0° C. is productive of 700mg of the white crystalline subject product.

EXAMPLE 76 Preparation ofd,l-erythro-1-iodo-3,4-bis-trimethylsilyloxy-trans-1-octene

To a stirred solution of 700 mg (2.40 mmol.) ofd,l-erythro-1-iodo-3,4-dihydroxy-trans-1-octene (Example 75) and 800 mg(12.0 mmol.) of imidazole, in 10 ml of dry dimethylformamide at 0° C. isadded dropwise 1.20 g (11.0 mmol.) of trimethylchlorosilane. The icebath is removed, and the mixture is stirred and heated at 50° C. forfive hours. It is then cooled, shaken with 50 ml of hexane and 50 ml ofwater, the organic layer separated and washed with 15 ml of 0.5 Mhydrochloric acid, 15 ml of a saturated solution of sodium bicarbonate,dried with magnesium sulfate, and evaporated. This crude product isfractionally distilled, bp 90°-92° C. (0.40 mm) to yield 250 mg of acolorless oil.

EXAMPLE 77 Preparation ofd,l-erythro-3-trimethylsilyloxy-4-ethoxy-1-iodo-tranns-1-octene

Following the procedure of Example 71, ethylation using iodoethane ofd,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne for a period of 22hours is productive of the correspondingd,l-erythro-3-tetrahydropyranyloxy-4-ethoxy-1-octyne. This intermediateis converted tod,l-erythro-3-tetrahydropyranyloxy-4-ethoxy-1-iodo-trans-1-octene whentreated successively with disiamylborane, trimethylamine oxide, iodine,and sodium hydroxide solution after the procedure of Example 72. Acidhydrolysis by the method of Example 18 tod,l-erythro-3-hydroxy-4-ethoxy-1-iodo-trans-1-octene, followed bytreatment with chlortrimethylsilane and imidazole in dimethylformamideusing the procedure of Example 74, and subsequent distillation, isproductive of the subject compound.

EXAMPLES 78-82

By the method of Example 58 reaction of1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne with n-butyllithiumand subsequent treatment with the aldehydes listed in Table 7, below,provides thed,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkynesof the table.

                                      TABLE 7                                     __________________________________________________________________________                    Product d,1-erythro-3-tetrahydropyranyloxy-                   Example                                                                            Starting Aldehyde                                                                        4-hydroxy-1-trimethylsilyl-1-alkyne                           __________________________________________________________________________    78   n-buanal  d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-1-heptyne                                              79   n-hexanal d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-1-nonyne                                               80   n-heptanol                                                                              d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-1-decyne                                               81   4-methyl-n-pentanal                                                                     d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-7-methyl-1-octyne                                      82   2-trans-n-pentenal                                                                      d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                        hydroxy-5-trans-en                                             __________________________________________________________________________

EXAMPLES 83-87

Hydrolysis of the 3-tetrahydropyranyloxy group of thed,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkyneslisted in Table 8 below by the method described in Example 59, followedby conversion of the resultingd,l-erythro-1-trimethylsilyl-3,4-dihydroxy-1-alkyne to the correspondingd,l-erythro-1-trimethylsilyl-3,4-isopropylidenedioxy-1-alkyne bytreatment with dimethoxypropane in the presence of perchloric acid bythe method described in Example 60, followed by desilylation to thecorresponding d,l-erythro-3,4-isopropylidenedioxy-1-alkyne by theprocedure of Example 61 followed by treatment with disiamylborane,trimethylamine oxide, iodine, and sodium hydroxide solution by themethod described in Example 62 provides the productd,l-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-alkenes of Table 8,below.

                                      TABLE 8                                     __________________________________________________________________________         Startind d,1-erythro-1-trimethyl-                                             silyl-3-tetrahydropyranyloxy-4-                                                               Product d,1-erythro-1-iodo-3,4-iso-                      Example                                                                       hydroxy-1-alkyne of Example                                                        propylidenedioxy-trans-1-alkene                                          __________________________________________________________________________    83   78              d,1-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-trans-1-heptene                                84   79              d,1-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-trans-1-nonene                                 85   80              d,1-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-trans-1-decene                                 86   81              d,1-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-7-methyl-trans-1-octene                        87   82              d,1-erythro-1-iodo-3,4-isopropyli-                                            denedioxy-trans,trans-1,5-octadiene                      __________________________________________________________________________

EXAMPLES 88-92

Acetylation of the 4-hydroxy group of thed,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkyneslisted in Table 9 below by the method described in Example 63, followedby hydrolysis of the resultingd,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-acetyloxy-1-alkynesto the correspondingd,l-erythro-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by themethod of Example 65, followed by epimerization tod,l-threo-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by the methodof Example 66 followed by hydrolysis by the method of Example 67 to gived,l-threo-3,4-dihydroxy-1-alkynes are converted to the correspondingd,l-threo-3,4-isopropylidenedioxy-1-alkynes by treatment withdimethoxypropane in the presence of perchloric acid by the methoddescribed in Example 68 followed by treatment with disiamylborane,trimethylamine oxide, iodine, and sodium hydroxide solution by themethod described in Example 62 provides the productd,l-threo-3,4-isopropylidenedioxy-trans-1-alkenes of Table 9 below.

                                      TABLE 9                                     __________________________________________________________________________         Starting d,1-erythro-1-trimethyl-                                             silyl-3-tetrahydropyranyloxy-4-                                                               Product d,1-threo-1-iodo-3,4-iso-                        Example                                                                       hydroxy-1-alkyne of Example                                                        propylidenedioxy-trans-1-alkene                                          __________________________________________________________________________    88   78              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                trans-1-heptene                                                               89   79              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                trans-1-nonene                                                                90   80              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                trans-1-decene                                                                91   81              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                trans-1,7-methyl-1-octene                                                     92   82              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                trans-1,5-trans-1-octadiene                                                   __________________________________________________________________________

EXAMPLE 93 Preparation of 1-octyn-4-ol

A suspension of 24.3 g (1.0 mole) of magnesium in 90 ml of dry ether isstirred at room temperature under nitrogen with 100 mg of mercuricchloride. The reaction is initiated by the addition of 2 ml of propargylbromide and maintained by the dropwise addition of a solution of 119.5 g(1.0 mole) of propargyl bromide and 107.7 g (1.25 mole) of valenaldehydein 300 ml of dry ether. While the initial reaction is quite vigorous andis maintained at 30° C. only by cooling in an ice bath it may becomenecessary to heat the mixture to reflux temperature after about a thirdof the ether solution is added in order to maintain the reaction. Afterthe addition is complete the reaction mixture is refluxed until most ofthe magnesium is dissolved (several hours) and the reaction mixture isdecanted from excess magnesium into 1500 ml of stirred ice-cold ammoniumchloride solution. The ether layer is separated and the aqueous layer isextracted three times with 300 ml portions of ether. The combined etherextract is washed with saturated sodium chloride solution, dried overmagnesium sulfate and filtered. Evaporation of the ether under vacuumleaves about 115 g of yellow oil, which is distilled through a 15 cmVigreaux column at 18 mm. The fraction boiling at 81°-82° C. iscollected (36 g) and the higher-boiling and lower-boiling distillatesmay be redistilled to yield additional product. The infrared absorptionspectrum shows at most a trace of allene (5.1μ) and gas-liquid partitionchromatography shows a purity of about 98% for the main fraction.

EXAMPLES 94-97

The product 1-alkyn-4-ols of Table 10 below are prepared by treatment ofthe aldehydes listed in Table 10 with propargyl magnesium bromide by theprocedure described above in Example 93.

                  TABLE 10                                                        ______________________________________                                                                   Product                                            Example   Starting Aldehyde                                                                             1-alkyn-4-ol                                        ______________________________________                                        94        n-hexaldehyde   1-nonyn-4-ol                                        95        n-heptaldehyde  1-decyn-4-ol                                        96        n-butyraldehyde 1-heptyn-4-ol                                       97        3-cis-hexenaldehyde*                                                                          4-hydroxy-6-cis-                                    ene-1-nonyne                                                                  ______________________________________                                         *M. Winter, Helv. Chim. Acta, 46, 1792 (1963).                           

EXAMPLE 98 Preparation of 4-triphenylmethoxy-1-octyne

A mixture of 10 g (0.08 moles) of 4-hydroxy-1-octyne [L. Crombie and A.G. Jacklin, J. Chem. Soc., 1632 (1957), also Example 93] and 30.75 g(0.09 moles) of triphenylmethyl bromide in 85 ml of dry pyridine isheated on the steam bath for 2 hours. The cooled mixture is treated withwater and extracted with ether. The extract is washed successively withice cold 2% hydrochloric acid, saturated sodium chloride solution, driedwith magnesium sulfate, and taken to dryness. Column chromatography ofthe residue on Florisil affords an oil; λ max 3.01, 4.72 (acetylenichydrogen), 6.28, 9.65 and 14.25μ (triphenylmethoxy group).

EXAMPLE 99 Preparation of 4-triphenylmethoxy-1-hexyne

A stirred solution of 9.81 g (0.10 moles) of 4-hydroxy-1-hexyne and 33.5g (0.12 moles) of triphenylmethyl chloride in 100 ml of dry pyridine isheated at reflux for 2 hours. The cooled mixture is treated with waterand extracted with a hexane-ether mixture. The extract is washedsuccessively with water and saturated sodium chloride solution, driedover magnesium sulfate, and concentrated. Column chromatography of theresidue on Florisil gives an oil, max. 3290 (acetylenic hydrogen), 1600,1030 and 705 cm⁻¹ (triphenylmethoxy group).

EXAMPLES 100-106

The triphenylmethoxy substituted 1-alkynes listed in Table 11 below areprepared by the method of Example 98 from triphenylmethyl bromide andthe corresponding hydroxy substituted 1-alkynes, appropriate literaturereferences to which are provided in the table.

                  TABLE 11                                                        ______________________________________                                             Reference to Starting                                                                            Product Triphenylmethoxy                              Ex.  Hydroxy Substituted 1-Alkyne                                                                     Substituted 1-Alkyne                                  ______________________________________                                        100  Reference 1        4-triphenylmethoxy-                                   1-pentyne                                                                     101  Reference 1        4-triphenylmethoxy-                                        (Example 96)                                                             1-heptyne                                                                     102  Reference 1        4-triphenylmethoxy-                                   5-methyl-1-hexyne                                                             103  Reference 2        4-triphenylmethoxy-                                        (Example 94)                                                             1-nonyne                                                                      104  Reference 3        4-triphenylmethoxy-                                        (Example 95)                                                             1-decyne                                                                      105  Reference 4        4-triphenylmethoxy-                                   5-ethyl-1-heptyne                                                             106  Example 97         4-triphenylmethoxy-                                   6-cis-ene-1-nonyne                                                            ______________________________________                                    

References

1. G. Fontaine, et al., Bull. Soc. Chem. France, 1447 (1963).

2. S. Abe and K. Sato, Bull. Soc. Chem. Japan, 29, 88 (1956); Chem.Abstr., 50, 13737 (1956).

3. L. Crombie and A. G. Jacklin, J. Chem. Soc., 1622 (1957);

4. Nobuharra, Akio, Chem. Abstr., 70, 3219 (1969).

EXAMPLE 107 Preparation of 1-iodo-4-triphenylmethoxy-trans-1-octene

To a stirred suspension of 1.78 g (0.074 mole) of sodium borohydriide in200 ml of dry glyme at -5° C. under nitrogen is added 15.8 g (0.22 mole)of 2-methyl-2-butene and 16.2 g (0.11 mole) of boron trifluorideetherate, and the mixture is stirred for 2 hours at -5° C. to 0° C. Asolution of 37.5 g (0.10 mole) of 4-trityloxy-1-octyne (Example 98) in50 ml of glyme is added to the cold solution during 5-10 minutes, andthe solution is allowed to warm to 20° C. during 1.5 hours. The reactionmixture is cooled to 0° C. and 30 g (0.4 mole) of drytrimethylamine-N-oxide is added during 5 minutes. On removing thecooling bath the temperature rises to 40° C. and the mixture is keptbetween 30°-40° C. for 1.5 hours. The suspension is poured rapidly intoone liter of ice cold 15% sodium hydroxide solution during good stirringand a solution of 80 g of iodine in 200 ml of tetrahydrofuran is addedimmediately. Stirring is continued for 30 minutes without furthercooling and the organic layer is separated. The aqueous layer isextracted with three 200 ml portions of ether and the combined organiclayers are washed successively with water, 5% sodium thiosulfatesolution and saturated sodium chloride, dried over magnesium sulfate,filtered and evaporated to yield 50 g of yellow oil. The bulk of the oilis dissolved in hexane and, after decantation from a gummy solid thehexane solution is percolated through a 5.1 cm diameter column of 1500 gof alumina with additional hexane. Fractions containing the desiredproduct are concentrated to a pale yellow oil (33 g) which has n.m.r.and infrared spectra characteristics of the desired product.

EXAMPLES 108-115

Treatment of the triphenylmethoxy substituted 1-alkynes listed in Table12 below with disiamylborane, prepared in situ from 2-methyl-2-butene,boron, trifluoride and sodium borohydride, followed by trimethylamineN-oxide, and then sodium hydroxide and iodine--all by the proceduredescribed in Example 107 above furnsihes the product triphenylmethoxysubstituted 1-iodo-1-trans-alkenes of the table.

                  TABLE 12                                                        ______________________________________                                                 Starting Triphenyl-                                                                           Product 1-Iodo-tri-                                           methoxy Substituted                                                                           phenylmethoxysubsti-                                 Example  1-Alkyne of Example                                                                           tuted-1-traans-alkene                                ______________________________________                                        108       99             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                     hexene                                                                        109      100             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                                              pentene                                              110      101             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                     heptene                                                                       111      102             1-iodo-4-triphenyl-                                                           methoxy-5-methyl-1-                                  trans-hexene                                                                  112      103             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                     nonene                                                                        113      104             1-iodo-4-triphenyl-                                                           methoxy-1-trans-                                     decene                                                                        114      106             1-iodo-4-triphenyl-                                                           methoxy-1-trans-6-                                   cis-nonadiene                                                                 ______________________________________                                    

EXAMPLES 116-124

The starting aldehydes or ketones of Table 13 below are converted to theproduct 1-alkyn-4-ols of the table by the procedure described in Example93.

                  TABLE 13                                                        ______________________________________                                             Starting                                                                 Ex.  Aldehyde or Ketone                                                                             Product 1-Alkyn-4-ol                                    ______________________________________                                        115  2-octanone      4-methyl-4-hydroxy-1-decyne                              116  trans-2-hexenal 4-hydroxy-5-trans-nonen-1-yne                            117  2,2-dimethylhexanal                                                                           5,5-dimethyl-4-hydroxy-1-nonyne                          118  2-heptanone     4-methyl-4-hydroxy-1-nonyne                              119  2,2-dimethylpentanal                                                                          5,5-dimethyl-4-hydroxy-1-octyne                          120  2-methylpentanal                                                                              5-methyl-4-hydroxy-1-octyne                              121  2-methylhexanal 5-methyl-4-hydroxy-1-nonyne                              122  2-hexanone      4-hydroxy-4-methyl-1-octyne                              123  trans-3-hexen-2-one.sup.a                                                                     4-hydroxy-4-methyl-5-trans-                              octen-1-yne                                                                   124  trans-2-pentenal.sup.b                                                                        4-hydroxy-5-trans-octen-1-yne                             124a                                                                              trans-2-heptenal.sup.b                                                                        4-hydroxy-5-trans-decen-1-yne                            ______________________________________                                         a G. Sturtz, Bull. Soc. Chim. Fr., 1967, 2477.                                b R. I. Hoaglin and D. N. Hirsh, U.S. 2,628,257; Chem. Abstr., 48, 1423e      (1954).                                                                  

EXAMPLE 125 Preparation of 4-methyl-4-trimethylsilyloxy-1-octyne

To a stirred solution of 75.4 g (0.537 moles) of4-hydroxy-4-methyl-1-octyne (Example 122γ, 104.9 g (1.54 moles) ofimidazole, and 325 ml of dimethylformamide is added 65.2 g (0.60 moles)of chlorotrimethylsilane. After standing overnight the mixture is pouredinto 800 ml of hexane. The mixture is washed thoroughly with waterfollowed by sodium bicarbonate solution and brine. The solution is driedover magnesium sulfate, filtered, and evaporated to give a liquid,p.m.r. spectrum, δ 1.26 (singlet, 3, CH₃), 1.92 (triplet, 1, HC), 2.30(doublet, 2, CH₂).

EXAMPLES 126-129

The 1-alkyn-4-ols of Table 14 are converted to the producttrimethylsilyl ethers of the table by treatment withchlorotrimethylsilane according to the procedure described in Example125.

                                      TABLE 14                                    __________________________________________________________________________    Example                                                                             Starting 1-Alkyn-4-ol                                                                       Product Trimethylsilyl Ether                              __________________________________________________________________________    126  5,5-dimethyl-4-hydroxy-1-                                                                   5,5-dimethyl-4-trimethylsilyloxy-1-nonyne                       nonyne (Ex. 117)                                                         127  4-methyl-4-hydroxy-1-nonyne                                                                 4-methyl-4-trimethylsilyloxy-1-nonyne                           (Ex. 118)                                                                128  5,5-dimethyl-4-hydroxy-1-                                                                   5,5-dimethyl-4-trimethylsilyloxy-1-octyne                       octyne (Ex. 119)                                                         129  4-hydroxy-4-methyl-5-trans-                                                                 4-methyl-4-trimethylsilyloxy-5-trans-                           octen-1-yne (Ex. 123)                                                                       octen-1-yne                                                 129a                                                                              4-hydroxy-4-methyl-1-decyne                                                                 4-methyl-4-trimethylsilyloxy-1-decyne                           (Ex. 124a)                                                               __________________________________________________________________________

EXAMPLE 130 Preparation of 1-iodo-4-hydroxy-4-methyl-trans-1-octene

To a stirred solution of 400 ml of 0.5 M bis-(3-methyl-2-butyl)borane inglyme, prepared from sodium borohydride, 2-methyl-2-butene, andboronitrifluoride etherate as in Example 107, is added 63.7 g (0.30moles) of 4-methyl-4-trimethylsilyloxy-1-octyne (Example 125) at -10° C.The solution is stirred at ambient temperature for 2.5 hours, cooled to-10° C., and treated during 30 minutes with 158 g (2.1 moles) of solidtrimethylamine oxide with cooling. The mixture is stirred at ambienttemperature for 2 hours and then poured into a stirred, ice-coldsolution of 15% aqueous sodium hydroxide; the stirred mixture is treatedimmediately with a solution of 426 g (1.68 moles) of iodine in 1100 mlof tetrahydrofuran. After 4 hours the mixture is extracted with ether.The extract is washed successively with water, aqueous sodiumthiosulfate, and brine and dried over magnesium sulfate. The extract isconcentrated, and the residue is subjected to chromatography on silicagel with hexane to provide an oil, p.m.r. (CDCl₃): δ 1.18 (singlet,4-CH₃ group).

EXAMPLES 131-134

The 4-trimethylsilyloxy-1-alkynes of Table 15 are converted to the4-hydroxy-1-iodo-trans-1-octenes of the table by the procedure describedin Example 130.

                  TABLE 15                                                        ______________________________________                                                Starting 4-Tri-                                                               methylsilyloxy-                                                               1-octyne of  Product 4-Hydroxy-1-iodo-                                Example Example      trans-1-octene                                           ______________________________________                                        131     126          1-iodo-5,5-dimethyl-4-hy-                                                     droxy-trans-1-nonene                                     132     127          1-iodo-4-methyl-4-hydroxy-                                                    trans-1-nonene                                           133     128          1-iodo-5,5-dimethyl-4-hy-                                                     droxy-trans-l-octene                                     134     129          1-iodo-4-methyl-4-hydroxy-                                                    trans,trans-1,5-octadiene                                 134a    129a        1-iodo-4-methyl-4-hydroxy-                                                    trans-1-decene                                           ______________________________________                                    

EXAMPLE 135 Preparation of1-iodo-4-methyl-4-trimethylsilyloxy-trans-1-octene

To a stirred mixture of 24.5 g (55.6 mmoles) of1-iodo-4-hydroxy-4-methyl-trans-1-octene (Example 130), 13.6 g (200mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g(100 mmoles) of chlorotrimethylsilane. After standing overnight themixture is poured into 250 ml of hexane. The mixture is washedthoroughly with water followed by brine and dried over magnesiumsulfate. After removal of the solvent, the product is distilled to givea colorless liquid, bp 67.5°-68° C. (0.07 mm).

EXAMPLES 136-139

The 1-iodo-4-hydroxy-trans-1-alkenes of Table 16 are converted to theproduct trimethylsilyl ethers of the table according to the proceduredescribed in Example 135.

                  TABLE 16                                                        ______________________________________                                                Starting 1-Iodo-4-                                                            hydroxy-trans-1-                                                                             Product Trimethylsilyl                                 Example alkene of Example                                                                            Ether                                                  ______________________________________                                        136     131            1-iodo-5,5-dimethyl-4-                                                        trimethylsilyloxy-                                                            trans-1-nonene                                         137     132            1-iodo-r-methyl-4-tri-                                                        methylsilyloxy-trans-                                                         nonene                                                 138     133            1-iodo-5,5-dimethyl-4-                                                        trimethylsilyloxy-                                                            trans-1-octene                                         139     134            1-iodo-4-methyl-4-tri-                                                        methylsilyloxy-trans,-                                                        trans-1,5-octadiene                                     139a    134a          1-iodo-4-methyl-4-tri-                                                        methylsilyloxy-trans-1-                                                       decene                                                  139b    134b          1-iodo-4-methyl-4-tri-                                                        methylsilyloxy-trans-1-                                                       decene                                                 ______________________________________                                    

EXAMPLE 140 Preparation of 4-benzoyloxy-1-octyne

To a stirred solution of 63. g (0.50 moles) of 1-octyn-4-ol (Example 93)in 500 ml of pyridine is added 77 g (0.55 moles) of benzoyl chloride.After stirring for 1.5 hours the mixture is treated with 10 ml of water,allowed to stand for 15 minutes, and concentrated. A solution of theresidue in ether is washed successively with ice-cold hydrochloric acid,water, sodium bicarbonate solution, and brine. The solution is driedover magnesium sulfate, filtered through Celite, and concentrated togive an oil, λ max. 3240 (terminal acetylene) and 1730 cm⁻¹ (benzyloxygroup).

EXAMPLE 141 Stereoselective Hydrolysis of Racemic 4-benzoyloxy-1-octyneby Rhizopus arrhizus

An agar slant of R. arrhizus (MUMF 1638) is used to inoculate 7 shakeflasks (250 ml Erlenmeyer). Each flask contains, 50 ml of a mediumconsisting of 2% Edamine, 2% glucose, and 0.72% corn steep liquor inwater with pH adjusted to 7.0. A total of 14 such flasks are incubatedon a rotary shaker at 28° C. After 72 hours incubation, 50 mg of racemic4-benzoyloxy-1-octyne (Example 135) in 0.1 ml of acetone is added toeach flask. After 28 hours the flasks are harvested and worked up byextraction of the whole mash with an equal volume of chloroform. Thecombined extracts are dried over magnesium sulfate and concentrated. Theresulting oil is chromatographed on a column of silica gel with hexaneprogressively enriched in ethyl acetate.

From fractions 3-6 is obtained 150 mg of colorless oil, identical to4-benzoyloxy-1-octyne, [α]_(D) ²⁵ =5°±1.0° (C=0.91, ethyl acetate). Thiscompound has the (S)-configuration.

From fractions 13-20 is obtained 75 mg of colorless oil, identical to4-hydroxy-1-octyne, [α]_(D) ²⁵ =-17°±1.0° (C=0.77, ethyl acetate). Thiscompound has the (R)-configuration.

The strain of R. arrhizus utilized in this experiment is a higher funguswhich grows steadily on a variety of artificial media at 20°-25° C. Inthis study of the taxonomic aspects of the culture, Petri dishes ofpotato-dextrose, malt extract, and cornmeal agars were inoculated andincubated at ambient room temperature for 10 days. Observations ofcultural and morphological characteristics are recorded in thedescription below:

Colonies on Petri dishes of potato-dextrose agar growing rapidly,covering the agar surface in 3-5 days and producing a thick, loose matof grayish mycelium. Colony surface characterized by abundant blacksporangia. Colony reverse grayish white. Colonies on malt extract agargrowing rapidly, covering the agar surface in 3-5 days. Mycelial matthick, grayish-yellow. Colony surface becoming brownish-black frommasses of sporangia. Colony reverse, yellowish. Colonies on cornmealagar very thin, whitish; spreading across agar surface. Culturestransparent with relatively few sporangia produced. Visibility ofmicromorphology is good on this medium. Rhizoids produced sparinglyalong stoloniferous hyphae. Generally two to three sporangiophores arosefrom rhizoids. Walls of sproangiophores olive brown, 14.0-20.0 μm inwidth at base, tapering slighly to apex; 0.5-1.5 mm in length.Sporangiophores terminated by spherical sporangia, 130-225 μm indiameter. Columellae hemispherical, 3-50 μm high by 50-80 μm wide.Spores brownish when mature, 6.0-8.5 μm×4.5-6.0 μm. Spore wallsconspicuously marked by longitudinal striations.

EXAMPLE 142 Preparation of (S)- 4-hydroxy-1-octyne

A solution of 1.15 g (5.0 mmoles) of (S)-4-benzoyloxy-1-octyne (Example141) and 1.40 g (25 mmoles) of potassium hydroxide in 50 ml of 10:1methanol-water is allowed to stand at room temperature for 24 hours. Thebulk of the methanol is evaporated at room temperature, and the mixtureis extracted with ether. The extract is washed with brine, dried overmagnesium sulfate, and evaporated to give a colorless oil, identical to4-hydroxy-1-octyne [α]_(D) ²⁵ =+17+1.0° (C=0.77, ethyl acetate). Thiscompound has the (S)-configuration.

EXAMPLES 143-148

The starting 1-alkyn-4-ols of Table 17 below are converted to thetriphenylmethoxy substituted 1-alkynes by the method of Example 98.

                  TABLE 17                                                        ______________________________________                                                               Product Triphenyl-                                             Starting 1-Alkyn-                                                                            methoxy Substituted                                    Example 4-ol of Example                                                                              1-Alkyne                                               ______________________________________                                        143     116            4-triphenylmethoxy-5-                                                         trans-nonen-1-yne                                      144     120            5-methyl-4-triphenyl-                                                         methoxy-1-octyne                                       145     121            5-methyl-4-triphenyl-                                                         methoxy-1-nonyne                                       146     124            4-triphenylmethoxy-5-                                                         trans-octen-1-yne                                      147     141            (R)-4-triphenylmeth-                                                          oxy-1-octyne                                           148     142            (S) -4-triphenylmeth-                                                         oxy-1-octyne                                            148a    124a          4-triphenylmethoxy-5-                                                         trans-decen-1-yne                                      ______________________________________                                    

EXAMPLES 149-154

The product triphenylmethoxy substituted 1-iodo-1-trans-alkenes of Table18 below are prepared from the starting triphenylmethoxy substituted1-alkynes of the table by the procedure described in Example 107.

                                      TABLE 18                                    __________________________________________________________________________         Starting Triphenyl-                                                           methoxy Substituted                                                                         Product Triphenylmethoxy Substituted                       Example                                                                            1-Alkyn of Example                                                                          1-Iodo-trans-1-alkene                                      __________________________________________________________________________    149  143           1-iodo-4-triphenylmethoxy-trans,trans-                                        1,5-nonadiene                                              150  144           1-iodo-5-methyl-4-triphenylmethoxy-                                           trans-1-octene                                             151  145           1-iodo-5-methyl-4-triphenylmethoxy-                                           trans-1-none                                               152  146           1-iodo-4-triphenylmethoxy-trans,trans-                                        1,5-octadiene                                              153  147           (R)-1-iodo-4-triphenylmethoxy-1-trans-                                        octene                                                     154  148           (S)-1-iodo-4-triphenylmethoxy-1-trans-                                        octene                                                      154a                                                                               148a         1-iodo-4-triphenylmethoxy-trans,trans-                                        1,5-dicadiene                                              __________________________________________________________________________

EXAMPLE 155 Preparation of ethyl-p-fluorophenoxy-acetate

To a stirred solution of 50 g (0.29 moles) of p-fluorophenoxy aceticacid in one liter of absolute ethanol is added 10 ml of sulfuric acid.The mixture is heated to reflux for 18 hours, cooled to roomtemperature, and evaporated under vacuum. It is then poured onto 300 gof ice, extracted twice with 500 ml of ether, washed twice with 250 mlof a saturated solution of sodium bicarbonate, 100 ml of saturatedsodium chloride solution, dried with magnesium sulfate, filtered andevaporated under vacuum giving 58 g of an oil. This is crystallized from50 ml of hexane at -25° C. to give 55 g (90%) of the subject product ascolorless crystals, mp 32°-33° C.

EXAMPLE 156 Preparation of p-fluorophenoxy acetaldehyde

To a stirred solution of 1.98 g (10 mmoles) of ethyl-p-fluorophenoxyacetate (Example 155) in 15 ml of dry toluene, cooled to -78° C., underargon, is added, dropwise over 30 minutes, 8 ml of a 1.4 M solution ofdiisobutylaluminum hydride in toluene (11 mmoles). The mixture isstirred for 2 hours at -78° C., 1 ml of methanol is added, followed by 5ml of water, dropwise. The gel formed is filtered through Celite andwashed with 100 ml of ether, portionwise. The organic phase isseparated, washed twice with 25 ml of a saturated brine solution, driedwith magnesium sulfate, filtered, and evaporated. The oil obtained isdistilled at 71°-73° C. (0.1 mm) to give 600 mg (45%) of the subjectproduct as a colorless liquid.

EXAMPLE 157 Preparation of 3-hydroxy-4-p-fluorophenoxy-1-butyne

Acetylene gas, dried by passing through a trap containing sulfuric acid,is bubbled at a moderate rate, through 5 ml of vigorously stirredtetrahydrofuran, for 15 minutes. To this acetylenic solution, is thenadded dropwise, with continued passage of acetylene, 3.5 ml of a 2.4 Msolution of n-butylmagnesium chloride in tetrahydrofuran (8.4 mmoles)over 45 minutes. The mixture is stirred a further 15 minutes, and asolution of 580 mg (3.9 mmoles) of p-fluorophenoxy acetaldehyde (Example156) in 3 ml of tetrahydrofuran is added dropwise over 15 minutes. Thissolution is stirred for 2 more hours, with passage of acetylene, pouredinto 50 ml of a saturated solution of ammonium chloride, extracted twicewith 50 ml of ether, washed with 10 ml of ammonium chloride solution,dried with magnesium sulfate, filtered, and evaporated. The crudesubject product is purified by sublimation at 75° C. (0.1 mm) for 5hours to give 330 mg (48%) of white crystals, mp 46°-47° C.

EXAMPLE 158 Preparation of4-p-fluorophenoxy-3-trimethylsilyloxy-1-butyne

To a 0° C. solution of 10 g (55 mmoles) of3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of drydimethylformamidee and 88 g (130 mmoles) of imidazole is added dropwise,with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture,while under an argon atmosphere, is stirred at room temperature for 18hours, and then poured into 150 ml of hexane and 100 ml of ice-water.Thhe organic phase is separated, washed with 50 ml of a brine solution,dried with magnesium sulfate, and evaporated under vacuum. This crudeproduct is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give12.2 g (91%) of the subject compound as a colorless oily liquid.

EXAMPLE 159 Preparation of1-tri-n-butylstannyl-4-p-fluorophenoxy-3-trimethylsilyloxy-trans-1-butene

A mixture of 2.52 g (10 mmoles) of3-trimethylsilyloxy-4-p-fluorophenoxy-1- butyne (Example 158), 2.91 g(10 mmoles) of tri-n-butyl-tin hydride, and 10 mg ofazobisisobutyronitrile is heated, under an argon atmosphere, withstirring, for 2 hours at 140° C. After cooling to room temperature, thecrude reaction mixture is fractionally distilled at 180°-185° C. (0.05mm), to give 4.6 g (85%) of the subject product as a colorless liquid.

EXAMPLES 160-162

The product esters of Table 19 below are obtained by the proceduredescribed in Example 155.

                  TABLE 19                                                        ______________________________________                                                Starting Aryloxy Product Aryloxy                                      Example Acid             Ethyl Ester                                          ______________________________________                                        160     p-chlorophenoxy- ethyl p-chlorophenoxy-                                       acetic acid      acetate                                              161     3,4-dichlorophe- ethyl-3,4-dichlorophe-                                       noxyacetic acid  noxyacetate                                          162     phenoxyacetic acid                                                                             ethyl phenoxyacetate                                 ______________________________________                                    

EXAMPLE 163 Preparation of ethyl-m-trifluoromethylphenoxy-acetate

A mixture of 100 g (0.618 mole) of α,α,α-trifluoro-m-cresol, 106 g(0.632 mole) of ethyl bromoacetate, 87.5 g (0.632 mole) of potassiumcarbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, andat room temperature for 18 hours. The mixture is filtered, evaporatedunder vacuum on a rotorary evaporator at 45° C. and at 85° C. (0.1 mm)to remove excess ethyl bromoacetate. The reaction mixture is taken up in500 ml of ether, washed three times with 100 ml each of 0.1 M potassiumcarbonate, once with 100 ml of water, 100 ml of 0.01 M hydrochloricacid, and 100 ml of water. It is then dried with magnesium sulfate,filtered and evaporated, giving 142 g of the crude product. This isfractionally distilled at 73°-75° C. (0.1 mm) to give 124 g of thepurified subject product as a colorless liquid.

EXAMPLES 164-166

The product esters of Table 20 are obtained by treating the startingphenols with ethyl bromoacetate by the procedure of Example 162.

                  TABLE 20                                                        ______________________________________                                        Example   Starting Phenol                                                                             Product Ester                                         ______________________________________                                        164       p-bromophenol ethyl p-bromophenoxy-                                                         acetate                                               165       4-t-butylphenol                                                                             ethyl 4-t-butylphenoxy-                                                       acetate                                               166       p-methoxyphenol                                                                             ethyl p-methoxyphenoxy-                                                       acetic acid                                           ______________________________________                                    

EXAMPLES 167-173

Following the procedure of Example 156, the starting esters of Table 21are treated with diisobutylaluminum hydride to provide the productaldehydes of the table.

                  TABLE 21                                                        ______________________________________                                        Example   Starting Ester                                                                            Product Aldehyde                                        ______________________________________                                        167       163         m-trifluoromethylphenoxy                                                      acetaldehyde                                            168       164         p-bromophenoxy acetalde-                                                      hyde                                                    169       165         4-t-butylphenoxy acetal-                                                      dehyde                                                  170       166         p-methoxyphenoxy acetalde-                                                    hyde                                                    171       160         p-chorophenoxy acetalde-                                                      hyde                                                    172       161         3,4-dichlorophenoxy acet-                                                     aldehyde                                                173       162         phenoxyacetaldehyde                                     ______________________________________                                    

EXAMPLES 174-180

Following the procedure of Example 156, treatment of the startingaldehyde of Table 22 with acetylene magnesium chloride provides theproduct alkynes of Table 22.

                  TABLE 22                                                        ______________________________________                                                  Starting                                                            Example   Aldehyde  Product Aryloxy Alkyne                                    ______________________________________                                        174       167       3-hydroxy-4-m-trifluoromethyl-                                                phenoxy-1-butyne                                          175       168       3-hydroxy-4-p-bromophenoxy-1-                             butyne                                                                        176       169       3-hydroxy-4-t-butylphenoxy-1-                             butyne                                                                        177       170       3-hydroxy-4-p-methoxyphenoxy-                             1-butyne                                                                      178       171       3-hydroxy-4-p-chlorophenoxy-                              1-butyne                                                                      179       172       3-hydroxy-4-(3,4-dichlorophe-                                                 noxy)-1-butyne                                            180       173       3-hydroxy-4-phenoxy-1-butyne                               180a     a         3-hydroxy-5-phenyl-1-pentyne                               180b     b         3-hydroxy-5-(p-chlorophenyl)-                             1-pentyne                                                                      180c     c         3-hydroxy-5-(p-methoxyphenyl)-                            1-pentyne                                                                      180d     d         3-hydroxy-5-(m-trifluorometh-                                                 ylphenyl)-1-pentyne                                       ______________________________________                                         a.hydrocinnamaldehyde.sup.1                                                   b.p-chlorohydrocinnamaldehyde.sup.1                                           c.p-methoxyhydrocinnamaldehyde.sup.1                                          d.m-trifluoromethylhydrocinnamaldehyde.sup.2                                  1)Billman, et al., Synthetic Communications, 1, 127-131 (1971).               2)Lednicer, Journ. Med. Chem., 11, 1258 (1968).                          

EXAMPLES 181-186

Treatment of the starting alkynes of Table 23 by the procedure ofExample 158 followed by treatment of the procedure of Example 159provides the product (E) 1-tri-n-butyltin-1-alkenes of the table.

                  TABLE 23                                                        ______________________________________                                             Starting                                                                 Ex.  Alkyne   Product (E)-1-tri-n-butyltin-1-alkene                           ______________________________________                                        180  174      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                 m-trifluoromethylphenoxy-1-butene                                             181  175      (E)-1-tri-n-butystannyl-3-trimethylsilyloxy-4-                  p-bromophenoxy-1-butene                                                       182  176      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                 t-butylphenoxy-1-butene                                                       183  177      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                 p-methoxyphenoxy-1-butene                                                     184  178      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                 p-chlorophenoxy-1-butene                                                      185  179      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-                   3,4-dichlorophenoxy-1-butene                                                  186  180      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                 phenoxy-1-butene                                                              186a  48      (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-                    trimethylsilyloxy-(Z)-6-octadiene                                             186b 180a     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                 phenyl-1-pentene                                                              186c 180b     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                 (p-chlorophenyl)-1-pentene                                                    186d 180c     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                 (p-methoxyphenyl)-1-pentene                                                   186e 180d     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                 (m-trifluoromethylphenyl)-1-pentene                                           ______________________________________                                    

EXAMPLE 187 Preparation of 1-chloro-1-octen-3-one

This compound is prepared according to the procedure of Price andPappalardo [C. C. Price and J. A. Pappalardo, Org. Syn., 32, 27 (1952)]from hexanoyl chloride, acetylene, and aluminum chloride in 94% yield,bp 51°-52° C. (0.1 mm); λ max 1680, 1595, 941 cm⁻¹.

EXAMPLE 188 Preparation of 1-iodo-1-octen-3-one

A mixture of 25 g (0.16 moles) of 1-chloro-1-octen-3-one (Example 187)and 35 g (0.23 moles) of sodium iodide in 200 ml of reagent acetone isstirred at the reflux temperature for 18 hours. The cooled mixture isfiltered and the mother liquor taken to dryness. The residual oil isdissolved in benzene and the solution is washed with 5% sodiumthiosulfate solution, saturated sodium chloride solution, dried andtaken to dryness. The residual oil is crystallized from hexane to give26 g of a white solid, mp 35°-37° C.; λ max 1670, 950 cm⁻¹.

EXAMPLE 189 Preparation of 3-hydroxy-1-iodo-3-methyl-1-octene

To a Grignard solution prepared from 1.05 g (0.41 moles) of magnesiumand 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether underargon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45ml of ether. The resulting solution is stirred at ambient temperaturefor one hour. After the addition of 75 ml of saturated ammonium chloridethe ether layer is separated and the aqueous layer is separated and theaqueous layer is extracted several times with ether. The coombined etherextracts are washed successively with ammonium chloride and water, driedand taken to dryness to give 9.24 g of product as an oil; λ max 2.89,3.23, 6.24 and 10.5.

EXAMPLE 190 Preparation of 1-iodo-3-methyl-3-trimethylsilyloxy-1-octene

To a stirred solution of 11.7 g of 3-hydroxy-1-iodo-3-methyl-1-octene(Example 184) and 7.4 g of imidazole in 45 ml of dry dimethylformamideis added dropwise 5.98 g of trimethylsilylchloride at 0° C. under argonatmosphere. After stirring at 0° C. for an additional 15 minutes, thesolution is stirred at ambient temperature for 18 hours. The reactionmixture is poured into 600 ml of hexane and the resulting solutionwashed with water, saturated sodium chloride solution, dried overanhydrous magnesium sulfate and taken to dryness to furnish 14.7 g ofoil. Distillation affords 13.4 g of clear oil; bp 65° C. (0.05 mm); λmax 6.21, 8.00, 9.90, 10.51, 11.90, 13.2μ.

EXAMPLE 190a Preparation of 1-iodo-3-methyl-3-trimethylsilyloxy-1-decene

Treatment of octanoylchloride by the procedures of Example 187 followedby treatment of the resulting 1-chloro-1-decen-3-one by the procedure ofExample 188 followed by treatment according to Examples 189 and 190 isproductive of the named compound.

EXAMPLE 191 Preparation of 4-trimethylsiloxy-1-octyne

To a cold solution of 166 g of 4-hydroxy-1-octyne [Prostaglandins, 10,289 (1975)], and 240 g of imidazole in one liter of dimethylformamide isadded dropwise 202 g of chlorotrimethylsilane. The mixture is allowed tostand at room temperature for 2 to 3 days. The mixture is partitionedwith water and hexane. The hexane layer is washed with brine, dried overmagnesium sulfate, and concentrated. Distillation of the residue gives acolorless liquid, bp 38° C. (0.2 mm).

EXAMPLE 192 Preparation of 1-iodo-4-trimethylsiloxy-trans-1-octene

To a stirred solution of 0.20 moles of freshely preparedbis-(3-methyl-2-butyl)borane in 300 ml of tetrahydrofuran at 0°-5° C. isadded dropwise a solution of 19.8 g of 4-trimethylsiloxy-1-octyne in 30ml of tetrahydrofuran. The resulting mixture is stirred at ambienttemperature for several hours, cooled in an ice bath, and treated with53 g of trimethylamine oxide. The mixture is stirred several hours at25°-40° C. and then poured into 2 liters of 15% sodium hydroxide. Theresulting mixture is treated immediately with a solution of 140 g ofiodine in 300 ml of tetrahydrofuran. After 0.5 hour the organic phaseis-separated and the aqueous phase is extracted with ether. The combinedorganic layers are washed with water, sodium thiosulfate solution, andbrine; dried over magnesium sulfate; and concentrated to give an oil,pmr spectrum (CDCl₃): 6.2 (d, ICH═) and 6.7 (quintuplet, ═CH--).

EXAMPLE 193 Preparation of 4-hydroxy-1-iodo-trans-1-octene

A 23 g portion of 1-iodo-4-trimethylsilyloxy-1-octene is dissolved in amixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and50 ml of water. Concentration provides the named product.

EXAMPLE 194 Preparation of4-trimethylsiloxy-4-vinyl-1-iodo-trans-1-octene

To a stirred solution of 456 mg of4-hydroxy-4-vinyl-1-iodo-trans-1-octene and 320 mg of imidazole in 1.0ml of dimethylformamide is added 0.23 ml of chlorotrimethylsilane during3 minutes. The mixture is stirred at room temperature for 22 hours andpartitioned with a mixture of cold hexane and water. The hexane layer iswashed repeatedly with water and then brine, dried over magnesiumsulfate, and concentrated to give an oil, pmr spectrum (CDCl₃): 0.13 (s,trimethylsiloxy group) and 2.32 (d, ═CHCH₂).

EXAMPLE 195 Preparation of n-butyl cyclopropyl ketone

To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylicacid in 330 ml of ether is added a solution of n-butyllithium (748mmoles) in about 750 ml of 2:1 ether-hexane during one hour at 5°-10° C.The resulting suspension is diluted with 300 ml of ether and stirred atroom temperature for 2 hours and at reflux for 2 hours. The mixture iscooled and poured into several portions of 1:1 ice:4 N hydrochloricacid. The ethereal phases are combined and washed with brine, sodiumcarbonate solution, and brine. The extract is dried over magnesiumsulfate and concentrated. The residue is distilled to provide a liquid,bp-102°-104° C. (80 mm), pmr spectrum (CDCl₃): δ 2.55 (triplet, --CH₂CO--).

EXAMPLE 196 Preparation of 4-cyclopropyl-4-hydroxy-1-octyne

To a stirred, refluxing suspension of amalgum prepared from 6.2 g ofmagnesium and 50 mg of mercuric chloride suspended in 60 ml of ether isadded a solution of a mixture of 30.4 g of n-butyl cyclopropyl ketone(Example 189) and 29.8 g of propargyl bromide in 65 ml of ether during60 minutes. After reaction at reflux temperature for an additional 30minutes, the mixture is cooled to 0° C. and treated with 35 ml ofsaturated ammonium chloride. The mixture is diluted with ether andfiltered through Celite. The filtrate is washed with brine, dried overpotassium carbonate, and concentrated. The resiidue is distilled toprovide a liquid, δ 0.43 (cyclopropyl hydrogens), 2.07 (triplet,HC.tbd.C), and 2.44 (doublet, C.tbd.CCH₂).

EXAMPLE 197 Preparation of 4-cyclopropyl-4-trimethylsiloxy-1-octyne

To a stirred solution of 27.8 g of 4-cyclopropyl-4-hydroxy-1-octyne(Example 190) and 33.3 g of imidazole in 130 ml of dimethylformamide at5° C. is added 24 ml of chlorotrimethylsilane during 5 minutes. Thesolution is stirred at ambient temperature for 17 hours and thenpartitioned with 600 ml of hexane and 250 ml of ice water. The hexanephase is separated and washed successively with water and brine. Thesolution is dried over magnesium sulfate and evaporated to give aliquid, pmr spectrum (CDCl₃): δ 0.12 (singlet, trimethylsiloxy group),2.02 (triplet, HC.tbd.C), and 2.45 (doublet, C.tbd.CH₂).

EXAMPLE 198 Preparation of4-cyclopropyl-4-trimethylsiloxy-1-(tri-n-butylstannyl)-trans-1-octene

A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-1-octyne(Example 191), 28 ml of tri-n-butyltin hydride, and 50 mg ofazobisisobutyronitrile under nitrogen is ehated to 85° C. After theresulting exothermic reaction subsides the mixture is heated at 130° C.for one hour. The crude product is evaporatively distilled to give aliquid, pmr spectrum (CDCl₃): δ 0.10 (trimethylsiloxy group), 2.33(doublet, ═CHCH₂), and 6.02 (vinyl hydrogens).

EXAMPLES 199-204

Treatment of the starting carboxylic acids of Table 24 with theappropriate alkyllithium by the method of Example 190 provides theproduct ketones of the table.

                                      TABLE 24                                    __________________________________________________________________________         Starting                                                                 Example                                                                            Carboxylic Acid                                                                        Alkyl Lithium                                                                         Product Ketone                                          __________________________________________________________________________    199  cyclopropane                                                                           n-hexyllithium                                                                        n-hexylcyclopropyl ketone                                    carboxylic acid                                                          200  cyclopropane                                                                           n-propyllithium                                                                       n-propylcyclopropyl ketone                                   carboxylic acid                                                          201  acrylic acid                                                                           n-hexyllithium                                                                        n-hexylvinyl ketone                                     202  acrylic acid                                                                           n-propyllithium                                                                       n-propylvinyl ketone                                    203  crotonic acid                                                                          n-butyllithium                                                                        n-butyl-1-propenyl ketone                               204  crotonic acid                                                                          n-hexyllithium                                                                        n-hexyl-1-propenyl ketone                               __________________________________________________________________________

EXAMPLES 205-210

Treatment of the starting ketones of Table 25 with propargymagnesiumbromide by the procedure of Example 190 followed by treatment withchlorotrimethylsilane by the procedure of Example 191 followed bytreatment with tri-n-butyltin hydride by the method of Example 192 isproductive of the vinylstannyl derivatives of the table.

                  TABLE 25                                                        ______________________________________                                               Starting                                                               Example                                                                              Ketone   Product Vinylstannyl Derivative                               ______________________________________                                        205    193      (E)4-trimethylsilyloxy-4-cyclopropyl-1-                       tri-n-butylstannyldecene                                                      206    194      (E)4-trimethylsilyloxy-4-cyclopropyl-1-                       tri-n-butylstannylheptene                                                     207    195      (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                       butylstannyldecene                                                            208    196      (E)t-trimethylsilyloxy-4-vinyl-1-tri-n-                                       butylstannylheptene                                           209    197      (E)4-trimethylsilyloxy-4-(1-propenyl)-1-                      tri-n-butylstannyloctene                                                      210    198      (E)4-trimethylsilyloxy-4-(1-propenyl)-1-                      tri-n-butylstannyldecene                                                      ______________________________________                                    

EXAMPLE 211 Preparation of 1-propargyl-1-hydroxycyclohexane

A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-l. ofanhydrous ether is treated with 0.6 g of mercuric chloride and about 100mg of iodine. After several minutes, 3 ml of propargyl bromide is addedand if no exotherm is noted, a small amount of reacting propargylbromide and magnesium in ether is added. When the reaction begins, amixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargylbromide is added dropwise at a rate that produces vigorous refluxing ofthe solution. (The propargyl bromide must always be present in someexcess otherwise the reaction will stop. If this happens, the additionof about 1 ml of propargyl bromide will restart the reaction.) Afterabout half of the propargyl bromide-cyclohexanone mixture has beenadded, another 500-750 ml of ether is used to dilute the reactionmixture. At the end of the addition, the reaction mixture is refluxedfor at least 0.5 hour, cooled and poured into 4 liters of saturatedammonium chloride during good stirring. The ethereal layer is separatedand the aqueous layer is washed with ether several times and thecombined extract is washed twice with saturated sodium chloride solutionand dried over anhydrous magnesium sulfate. Evaporation of the etheryields 583 g (630 g theory) of a dark oil which is distilled givingpurified 1-propargyl-1-hydroxycyclohexane.

EXAMPLE 212 Preparation of 1-Ethynyl-1-trimethylsilyloxycyclohexane

A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexan-1-ol aremixed with 500 g of dimethylformamide with cooling in an ice bath. A 152g portion of trimethylchlorosilane is added with cooling and stirring inabout one minute. The mixture is stirred for one hour and allowed tostand overnight. One liter of hexane is added. The lower layer isseparated, diluted with water and extracted with hexane. The hexanelayers are washed several times with water and then combined and driedover magnesium sulfate. Filtration and then evaporation of the hexanegives 198.5 g of product which is distilled giving 168 g of the desiredproduct.

EXAMPLE 213 Preparation of 1-Propargyl-1-trimethylsilyloxycyclohexane

To a stirred solution of 55.4 g of 1-(2-propyn-1-yl)cyclohexanol [H.Gutmann, et. al., Helv. Chim. Acta, 42, 719 (1959)] and 79 g ofimidazole in 240 ml of DMF at 10° C. initially is added 56 ml ofchlorodimethylsilane during 10 minutes. The cloudy yellow solution isstirred at room temperature for 26 hours. The resulting mixture ispartitioned between 1000 ml of hexane and 400 ml of water at 0°-5° C.The hexane phase is washed successively with 6×200 ml of cold water and200 ml of brine. The extract is dried over magnesium sulfate, filtered,and evaporated to give 85 g of colorless liquid, i.r. (film):1240 and830 cm⁻¹ (trimethylsilyloxy group).

EXAMPLE 214 Preparation of 1R,2S(and1S,2R)-1-Ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and1S,2S)-1-ethynyl- 1-hydroxy-2-butylcyclopentane

Into 150 ml of dry tetrahydrofuran is bubbled purified acetylene, as asolution of 2.4 M n-butyl magnesium chloride (92 ml) is added dropwisewith stirring over a 2 hour period. To the resulting solution ofacetylene magnesium chloride is added 21 g of 2-butylcyclopentanone in50 ml of tetrahydrofuran dropwise over 15 minutes. The solution isstirred for 30 minutes and then is poured into an ice cold solution ofsaturated ammonium chloride. The mixture is acidified to pH 5 andextracted with ether. The ether solution is washed with brine and driedover magnesium chloride. The ether is removed and the residue isdistilled giving 14.8 g of a colorless liquid. This is chromatographedon a dry column of silica-gel eluting with benzene-ethyl acetate (19:1)to separate isomers giving 1R,2S(and1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane.

EXAMPLE 215 Preparation of 1R,2S(and1S,2R)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a solution of 29.4 g of 1R,2S(and1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 30.2 g of imidazolein 180 ml of dimethylformamide is added at 0° C. with stirring 24.1 g oftrimethylsilylchloride. The mixture is stirred for 3 hours. The mixtureis poured into 700 ml of hexane and washed twice with water and oncewith brine. The ether solution is dried over magnesium sulfate. Thesolvent is removed and the residue is distilled (bp 64°-72° C., 0.6 mm)to give 35.8 g of 1R,2S(and1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane.

EXAMPLE 216 Preparation of 1R,2S(and1S,2R)-1-trans-2-Iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 9.2 g of sodium borohydride and 45.8 g of2-methyl-2-butene in 350 ml of dry tetrahydrofuran at 0° C. withstirring under nitrogen is added, over 20 minutes, 41.1 ml of borontrifluoride etherate. After 3 hours, to this resulting solution ofdiisoamylborane is added 38.8 g of 1R,2S(and1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 40 ml oftetrahydrofuran in 20 minutes. The mixture is ttirred 2 hours and thenstored at -20° C. overnight. The mixture is allowed to warm to 0° C. andat 0° C. 85 g of dry trimethylamineoxide is added portionwise over 20minutes. After stirring at 25° C. for one hour, the mixture is filteredthrough diatomaceous earth. The filtrate is poured simultaneously with asolution of 230 g of iodine in 250 ml of tetrahydrofuran into a stirred,cold solution of 430 g of sodium hydroxide in 1900 ml of water. Afterstirring for 30 minutes, the organic layer is separated. The aqueouslayer is extracted with ether. The combined organic solutions are washedtwice with a saturated solution of sodium thiosulfte and once withbrine. The solution is dried over magnesium sulfate, the solvent isremoved and the residue is dissolved in hexane. The hexane solution isfiltered through diatomaceous earth and silica gel. The hexane isremoved and the residue is purified by dry column chromatography onsilica gel eluting with hexane: 45.35 g of 1R,2S(and1S,2R)-1-(trans-2-iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane isobtained.

EXAMPLES 217-218

In the manner of Example 216 described above, the following acetylenicalcohols listed in Table 26 were prepared from the acetylenic Grignardreagent and the ketone specified.

                                      TABLE 26                                    __________________________________________________________________________    Example                                                                            Grignard Reagent                                                                         Ketone  Acetylenic Alcohol                                    __________________________________________________________________________    217  acetylene magnesium                                                                      cyclohexanone                                                                         1-ethynyl-1-hydroxycyclohexane                             chloride                                                                      Method A                                                                 218  aceylene magnesium                                                                       cyclopentanone                                                                        1-ethynyl-1-hydroxycyclopentane                            chloride                                                                      Method A                                                                 __________________________________________________________________________

EXAMPLE 219 Preparation of1-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane

To a stirred mixture of 31.5 g of1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg ofazobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. Thestirred mixture is heated to about 80° C. The initial exothermicreaction is moderated, and the temperature is subsequently maintained at130°-135° C. for one hour.

The product is distilled to afford 56 g of colorless liquid, bp150°-160° C. (0.15-0.3 mm), pmr (CDCl₃): 6.0 (multiplet, vinyl protons).

EXAMPLES 220-221

Using the procedure outlined above for Example 213, the acetylenicalcohols listed in Table 27 are converted to their correspondingacetylenic trimethylsilyloxy derivatives; these in turn using theprocedure outlined above for Example 216, were converted to theircorresponding trans-2-iodovinyl derivatives.

                  TABLE 27                                                        ______________________________________                                               Acetylene                                                              Example                                                                              of Example                                                                              Vinyl Iodide Compound                                        ______________________________________                                        220    217       1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                   cyclohexane                                                                   221    218       1-trans-2-iodovinyl)-1-trimethylsilyloxy-                    cyclopentane                                                                  ______________________________________                                    

EXAMPLE 222 Preparation of1-(3-Tri-n-butylstannyl)-2-trans-propenyl)-1-trimethylsilyloxycyclopentane

Treatment of cyclopentanone by the sequential reactions described byExamples 211, 213 and 219 is productive of the title compound.

EXAMPLE 223 Methyl Nat.15α-hydroxy-9-oxo-11α/β(2-hydroxyethylthio)-5-cis,13-trans-prostadienoate

A solution of 2 g of nat. PGA₂ methyl ester (U.S. Pat. No. 3,759,965)and 448 mg of 2-mercaptoethanol is stirred under argon. One drop oftriethylamine is added and the reaction mixture is stirred for 4 hoursand 15 minutes. A 180 mg portion of the reaction mixture ischromatographed on a one mm silica gel preparative plate, eluting withethyl acetate:benzene (2:3). A 2,4-dinitrophenylhydrazone positive band1/4 to 11/2 inches above the origin is removed and the product is elutedwith 20% methanol in chloroform. The eluate is evaporated giving 97 mgof the product (A) as a pale yellow oil.

The remainder of the reaction mixture is chromatographed similarly onfour silica gel preparative plates 2 mm thick. The product (B) isisolated as above and combined with (A) giving 1.55 g of the desiredproduct as a yellow oil.

EXAMPLE 224 11α/β-(2-hydroxyethylthio)-15-hydroxy-15-methyl-9-oxo-5-cis,13-trans-prostadienoic acid

A mixture of 200 mg of all racemic 15 methyl PGA₂ (U.S. Pat. No.3,919,286), 57 mg of mercaptoethanol and 60 mg of triethylamine isstirred under argon. One additional drop of triethylamine is added andthe mixture is stirred for 2 hours. The mixture is acidified with 5%HCl, extracted with ether, the ether is washed with a saturated solutionof sodium chloride and then dried over sodium sulfate. The residue ischromatographed on two 1 mm thick silica gel plates, eluting twice withethyl acetate:benzene (1:4) containing 1.5% acetic acid. The yellow2,4-dinitrophenylhydrazone positive band between 1/4 and 11/4 inchesabove the origin is removed from the silica with 20% methanol inchloroform, giving 143 mg of the desired product as an amber oil.

EXAMPLE 225 11α/β-(2-hydroxyethylthio)-16-hydroxy-16-methyl-9-oxo-5-cis,13-trans-prostadienoic acid

A solution of 4.2 g of E-1-iodo-4-methyl-4-trimethylsilyloxy-1-octene in100 ml of dry ether is cooled in a dry ice-acetone bath under nitrogenand treated with 30.85 ml of t-butyl lithium via a syringe, over aperiod of 15 minutes. In a second flask a mixture of 1.61 g of copperpentyne and 5.4 ml of hexamethylphosphoramide in 70 ml of ether isstirred for 15 minutes until it becomes clear. This copper pentynesolution is added to the vinyl lithium solution via a syringe, over aperiod of 20 minutes. The mixture is stirred in the same bath for 1.5hours and then a solution of 4.7 g of bis-THP-cyclopentenone in 70 ml ofether is added at -78° C. After stirring at -78° C. for 40 minutes, thecooling bath is replaced by an ice-acetone bath. Stirring is continuedat -20° C. to -10° C. for 40 minutes. The reaction is quenched by theaddition of 50 ml of cold, saturated aqueous ammonium chloride solutionand the entire mixture is poured into 450 ml of cold, saturated aqueousammonium chloride solution. The mixture is allowed to stand overnight ina refrigerator. The aqueous phase is separated and extracted twice withether. The ether extracts are combined with the organic phase and washedwith dilute aqueous HCl, water and finally brine. After evaporation ofthe solvents, the residue is dissolved in a mixture of 80 ml of aceticacid, 60 ml of tetrahydrofuran and 20 ml of water and stirred at roomtemperature for one hour. The mixture is poured into water and extractedwith ether. The ether extract is washed with brine and the solvents areevaporated on a rotary evaporator in the presence of toluene. Theresidue is passed through a 250 g silica gel column packed in 10% ethylacetate in hexane. Continuous elution with increasing percentage ofethyl acetate in hexane gives 2.33 g of product.

A 2.3 g portion of this product is dissolved in a mixture of 100 ml ofacetic acid, 50 ml of tetrahydrofuran and 25 ml of water. The mixture isstirred and heated at 45°-50° C. for 3.5 hours. The mixture is worked upby repeating the above ether extraction and water and brine washing. Thesolvent is evaporated in the presence of toluene as above. The residueis passed through a 50 g silica gel column packed in 30% ethyl acetatein hexane. Continuous elution with increasing percentage of ethylacetate in hexane give 1.09 g of product.

A solution of 157 mg of the above compound in 85 ml of tetrahydrofuranand 5 ml of 1.5 N HCl is stirred under a nitrogen atmosphere at roomtemperature for 48 hours. The reaction mixture is diluted with brine andextracted with 80 ml of ether in two portions. The combined etherextracts are washed with brine, dried over magnesium sulfate, filteredand concentrated in vacuo to a yellow oil. This oil is chrmatographedusing a 2000μ preparative thin layer plate, eluting with ethylacetate:benzene (2:3) containing 2% acetic acid. The product is locatedand then eluted from the silica gel with 20% methanol in chloroformgiving 122 mg of yellow oil.

To a stirred solution of the 122 mg of the previous compound, 56 mg ofβ-mercaptoethanol and one ml of tetrahydrofuran, at room temperature, isadded 14 drops of triethylamine. The reaction mixture is stirred for 3hours and then chromatographed using one 1 mm preparative thin layersilica gel plate, eluting with ethyl acetate:benzene (2:3) containing 2%acetic acid. The product is located and eluted from the silica gel with20% methanol in chloroform giving 52 mg of the desired product as ayellow oil.

EXAMPLE 22611α/β-(2-hydroxyethylthio)-16-hydroxy-9-oxo-13-trans-prostenoic acid

To a stirred solution of 8.57 g of(E)-1-tributylstannyl-4-triethylsilyloxy-1-octene and 10 ml of anhydroustetrahydrofuran, cooled to -70° C. under an argon atmosphere, is slowlyadded 7.0 ml of n-butyl lithium. After 15 minutes the reaction mixtureis warmed to -40° C. for 2 hours. The reaction mixture is recooled to-78° C. A solution of 2.2 g of copper pentyne and 6.85 g of tri-n-butylphosphine in 27 ml of ether is added. After 2 hours a 4.60 g portion ofcyclopentenone and 15 ml of anhydrous ether is added. After 30 minutes,the reaction mixture is warmed to -35° C.. to -40° C. for one hour andthen at 30° C. to 35° C. for 30 minutes. The reaction mixture is cooledto -40° C. and to it is slowly added 5 ml of acetic acid. The reactionmixture is poured into a mixture of 400 ml of saturated aqueous ammoniumchloride and 250 ml of ether and is vigorously stirred for one hour. Theaqueous phase is separated and extracted with 400 ml of ether in threeportions. The ether phases are combined, washed with 1% H₂ SO₄, driedover magnesium sulfate, filtered and concentrated in vacuo giving 22.7 gof amber liquid.

A solution of 22.7 g of the above liquid in 250 ml of a mixture ofacetic acid:tetrahydrofuran:water (4:2:1) is stirred under an argonatmosphere at room temperature for one hour. The reaction mixture isdiluted with toluene and concentrated in vacuo giving 19.7 g of brownliquid.

This 19.7 g of liquid is dry column chromatographed using 1500 g ofsilica gel and eluted with ethyl acetate:benzene (2:3) containing 2%acetic acid. A total of 900 ml is collected. The column is cut into oneinch segments, Like fractions are combined after thin layerchromatographic analysis. The product is eluted from the silica with 20%methanol in chloroform giving 1.6 g. An additional 326 mg was obtainedupon further chromatographing impure fractions.

A solution of 325 mg of the oil in 13 ml of tetrahydrofuran and 10 ml of1.5 N HCl is stirred under nitrogen, at room temperature for 48 hours.The reaction mixture is diluted with brine and extracted with 25 ml ofether in two portions. The combined ether extracts are washed withbrine, dried over magnesium sulfate, filtered and concentrated in vacuogiving a yellow oil.

This yellow oil is chromatographed using two 2000μ preparative thinlayer plates and eluting with ethyl acetate:benzene (2:3) containing 2%acetic acid. The product is located and eluted from the silica gel with20% methanol in chloroform giving 189 mg of a yellow oil.

To a stirred solution of the 189 mg of oil, 60 mg of β-mercaptoethanoland one ml of tetrahydrofuran at room temperature is added 17 drops oftriethylamine. The reaction mixture is stirred for 3 hours and thenchromatographed using one 1 mm preparative thin layer silica gel plateand eluting with ethyl acetate:benzene (2:3) containing 2% acetic acid.The product is located and eluted from the silica gel with 20% methanolin chloroform giving 111 mg of the desired final product as a yellowoil.

EXAMPLE 227Erythro-11α/β-(2-hydroxyethylthio)-15α,16-dihydroxy-9-oxo-5-cis,13-trans-prostadienoicacid

A 3.10 g portion of erythro(E)-1-iodo-3,4-isopropylidenedioxy-1-octeneis reacted with 29 ml of 0.8 N-t-butyllithium in hexane with 60 ml ofether for 2 hours. A solution in ether at -78° C. off 10 mmol of lithiumthiophenoxide with 3.95 g (10.0 mmol) of tri-n-butylphosphine copperiodide is next added for one hour, then is added 3.44 g of bis-THPcyclopentenone at -20° C. for 11/2 hours. The reaction mixture isquenched and worked up with ammonium chloride. This crude product ispartially deblocked with 125 ml of acetic acid:tetrahydrofuran:water(5:5:2) at room temperature for 2 hours. After removal of the solventsby azeotroping 3 times with toluene at 50° C., the crude product ischromatographed on a dry column of silica gel with 2:3 ethylacetate inbenzene with 2% of acetic acid. The column is cut into 11/2 inchsegments and like fractions are combined giving 2.10 g of product.

A solution of 400 mg of the above PG acetonide in 15 ml of aceticacid:tetrahydrofuran:water (4:2:1) is stirred at 50° C. under an argonatmosphere for 3 hours. The reaction mixture is cooled, diluted withtoluene and concentrated in vacuo giving a yellow oil.

This oil is stirred in a mixture of 15 ml of tetrahydrofuran and 12 mlof 1.5 N HCl under an argon atmosphere at room temperature for 48 hours.The reaction mixture is diluted with brine and extracted with 120 ml ofether in two portions. The combined ether extracts are washed withbrine, dried over magnesium sulfate, filtered and concentrated in vacuogiving a yellow oil. This oil is chromatographed using two 2000μpreparative thin layer silica gel plates, eluting with ethylacetate:benzene (2:3) containing 2% acetic acid. The product is locatedand eluted from the silica gel with 20% methanol in chloroform giving 88mg.

To a stirred solution of the above 88 mg of product, one ml oftetrahydrofuran and 126 mg of β-mercaptoethanol at room temperature, isadded 8 drops of triethylamine. The reaction mixture is stirred for 3hours and then chromatographed using one 2 mm preparative thin layerplate and eluting twice with ethyl acetate:benzene (2:3) containing 2%acetic acid. The product is located and eluted from the silica gel with20% methanol in chloroform. The eluent is concentrated in vacuo givingthe desired product as a yellow oil.

EXAMPLE 228 Nat.11α/β-(2-hydroxyethylthio)-15α-hydroxy-9-oxo-13-transprostenoic acid

To a mixture of 100 mg of nat. PGA₁ (U.S. Pat. No. 3,725,469) and 33 mgof triethylamine is added 24 mg of 2-mercaptoethanol. The reactionmixture is stirred under an argon atmosphere for 18 hours. Ether isadded. An equal volume of 5% HCl is added giving complete two-phasesolution. The ether is separated, washed three times with saturatedsodium chloride solution, dried over sodium sulfate and taken to drynessgiving a pale yellow oil comprising 123 mg of the desired product.

Column chromatography as described in Example 229 will provide theseparated 11α and 11β epimers.

EXAMPLE 229 MethylNat.-11α(2-hydroxyethylthio)-15α-hydroxy-9-oxo-5-cis,13-trans-prostadienoateand methyl nat.-11β(2-hydroxyethylthio)-15α-hydroxy-9-oxo-5-cis,13-transprostadienoate

A solution of 10 g (28.7 mmol) of nat.-PGA₂ methyl ester, 2.24 g (28.7mmol) of 2-mercaptoethanol and 5 drops of triethylamine is stirred atambient temperature under an argon atmosphere for 18 hours. Theresulting oil is chromatographed on a 61 inch by 3 inch (flat) nylontube packed with 1700 g of silica-gel. The column is developed withethyl-acetate-benzene-acetic acid (20:30:1), and 2000 ml of eluant iscollected. The column is then divided into 1-inch segments. Segments12-17 are combined to furnish 2.64 g ofnat.-11α-(2-hydroxyethylthio)-PGE₂ methyl ester; R_(f) 0.33(ethylacetate-benzene-acetic acid/20:30:1, 3 elutions). Segments 18-33are combined to give 2.83 g of a mixture of nat.-11α- and11β-(2-hydroxyethylthio)-PGE₂ methyl ester; R_(f) 0.33, 0.26 (ethylacetate-benzene-acetic acid/20:30:1, 3 elutions). Segments 24-36 arecombined to give 2.46 g of nat.-11β-(2-hydroxyethylthio)-PGE₂ methylester; R_(f) 0.26 (ethylacetate-benzene-acetic acid/20:30:1, 3elutions).

EXAMPLES 230-262

Additon of 2-mercaptoethanol to the A-prostaglandins of Table 28 by themethod of Example 229 followed by silica-gel chromatography isproductive of the separated 11α and 11β(2-hydroxyethylthio) prostanoicanalogs.

                                      TABLE 28                                    __________________________________________________________________________    Example                                                                       __________________________________________________________________________    230  nat.-prostaglandin A.sub.1                                                                 nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-13-                                                     trans-prostenoic acid and the corresponding 11β-isomer                   231  prostaglandin A.sub.1                                                                      11α-(2-hydroxyethylthio)-15α-hydroxy-9-oxo-1                      3-trans-                                                    prostenoic acid and the corresponding 11β-isomer                         232  nat.-prostaglandin A.sub.2                                                                 nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-5-cis,                                                                    13-trans-prostadienoic acid and the corresponding                             11β-                                                   isomer                                                                        233  prostaglandin A.sub.2                                                                      11α-(2-hydroxyethylthio)-15α-hydroxy-9-oxo-5                      -cis,13-                                                    trans-prostenoic acid and the corresponding 11β-                         isomer                                                                        234  15-deoxy-16-hydroxy                                                                        Ethyl 11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-13                      -trans-                                                          prostaglandin A.sub.1                                                    prostnoate and the corresponding 11β-isomer                                   ethyl ester (U. S.                                                            Patent 3,950,406)                                                        235  15-deoxy-16-hydroxy                                                                        Methyl 11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-1                      3-                                                               prostaglandin A.sub.1                                                    trans-prostenoate and the corresponding 11β-isomer                            methyl ester (U. S.                                                           Patent 3,950,406)                                                        236  15-deoxy-16-hydroxy-17-                                                                    11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-17-methy                      l-                                                               methyl-19,20-dinor                                                       19,20-dinor-13-trans-prostenoic acid and the                                       prostaglandin A.sub.1                                                                      corresponding 11β-isomer                                    (U.S. Patent 3,950,406)                                                  237  15-deoxy-16-hydroxy-17-                                                                    11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-17-ethyl                      -20-                                                             ethyl-20-nor                                                             nor-13-trans-prostenoic acid and the corresponding                                 prostaglandin A.sub.1                                                                      11β-isomer                                                  (U.S. Patent 3,950,406)                                                  238  nat.-15-deoxy-16(R)-                                                                       nat.-11α-(2-hydroxyethylthio)-16(R)hydroxy-9-oxo-1                      3--                                                         hydroxy prostaglandin A.sub.1                                                 trans-prostenoic acid methyl ester and the corresponding                           methyl ester 11β-isomer                                                  (U.S. Patent 3,950,406)                                                  239  nat.-15-deoxy-16(S)-                                                                       nat.-11α-(2-hydroxyethylthio)-16(S)-hydroxy-9-oxo-                      13-                                                         hydroxy prostaglandin A.sub.1                                                 trans-prostenoic acid methyl ester and the corresponding                           methyl ester 11β-isomer                                                  (U.S. Patent 3,950,406)                                                  240  15-deoxy-16-hydroxy-17-                                                                    11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-17-methy                      l-13-                                                       methyl-prostaglandin A.sub.1                                                  trans-prostenoic acid and the corresponding 11β-isomer                        Example 273                                                              241  15-deoxy-16-hydroxy-17-                                                                    ethyl 11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-17                      -                                                           methyl prostaglandin A.sub.1                                                       methyl-13-trans-prostenoate acid and the corresponding                        ethyl ester (Example 274)                                                                  11β-isomer                                             242  15-deoxy-16-hydroxy                                                                        11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-13-trans                      -                                                                prostaglandin A.sub.1                                                    prostenoic acid and the corresponding 11β-isomer                              (Example 275)                                                            243  15-deoxy-16-hydroxy-20-                                                                    11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-13,17-tr                      ans-                                                        nor-17-trans-prosta-                                                               prostadienoic acid and the corresponding 11β-isomer                      glandin A.sub.1 (Example 276)                                            244  nat.-16,16-trimethylene                                                                    nat.-methyl 11α-(2-hydroxyethylthio)-15α-hyd                      roxy-9-oxo-                                                      prostaglandin A.sub.1                                                    16,16-trimethylene-13-trans-prostenoate and the                                    Methyl ester (Example 267)                                                                 corresponding 11β-isomer                               245  nat. 16,16-trimethylene                                                                    nat.-methyl 11α-(2-hydroxyethylthio)-15α-hyd                      roxy-9-oxo-                                                      prostaglandin A.sub.2 methyl                                                               16,16-trimethylene-5-cis,13-trans-prostadienoic acid                          and                                                              ester (Example 268)                                                                        the corresponding 11β-isomer                           246  nat.-16,16-trimethylene                                                                    nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-16,16-                                                       prostaglandin A.sub.2                                                    trimethylene-5-cis,13-trans-prostadienoic acid and the                             (Example 269)                                                                              corresponding 11β-isomer                               247  nat.-16,16-trimethylene                                                                    nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-16,16-                                                       prostaglandin A.sub.1                                                    trimethylene-13-trans-prostenoic acid and the                                      (Example 270)                                                                              corresponding 11β-isomer                               248  nat.-16,16-trimethylene-                                                                   nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-16,16-tri-                                                   20-methyl prostaglandin                                                                    methylene-20-methyl-5-cis,13-trans-prostadienoic acid                         and                                                              A.sub.2 (Example 271)                                                                      the corresponding 11β-isomer                           249  nat.-16,16-trimethylene-                                                                   nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-16,16-tri-                                              20-ethyl-prostaglandin                                                             methylene-20-ethyl-5-cis,13-trans-prostadienoic acid and                      A.sub.2 (Example 272)                                                                      the corresponding 11β-isomer                           250  15-deoxy-16-hydroxy                                                                        11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-13-trans                      -prostenoic                                                      prostaglandin A.sub.1 (U.S.                                                                acid and the corresponding 11β-isomer                       Patent 3,965,143)                                                        251  15-deoxy-16-hydroxy-16-                                                                    methyl-11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-1                      6-methyl,                                                   methyl prostaglandin A.sub.1 3                                                     13-trans-prostenoate acid and the corresponding 11β-isomer               methyl ester (U.S. Patent                                                     3,965,143)                                                               252  nat.-15-methyl                                                                             methyl-nat.-11α-(2-hydroxyethylthio)-15α-hyd                      roxy-9-oxo-15-                                                   prostaglandin A.sub.1                                                    methyl,13-trans-prostenoate and the corresponding 11β-isomer                  Methyl ester                                                             253  nat.-15-methyl-                                                                            methyl-nat.-11α-(2-hydroxyethylthio)-15α-hyd                      roxy-9-oxo-15-                                              prostaglandin A.sub.2                                                         methyl-5-cis,13-trans-prostadienoate and the corresponding                    Methyl ester                                                                       11β-isomer                                                          254  nat.-16,16-dimethyl                                                                        nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9o                      xo-16,16-                                                        prostaglandin A.sub.2                                                    dimethyl-5-cis,13-trans-prostadienoic acid and the                                              corresponding 11β-isomer                               255  nat.-16(S)-methyl                                                                          nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-16(S)-methyl-                                                prostaglandin A.sub.2                                                    5-cis,13-trans-prostadienoic acid and the corresponding                                         11β-isomer                                             256  nat.-        nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-5-cis,13-                                                    prostaglandin A.sub.3                                                    transk17-trans-prostatrienoic acid and the corresponding                           (Example 265)                                                                              11β-isomer                                             257  nat.-20-methyl                                                                             nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-20-methyl-5-                                                 prostaglandin A.sub.2                                                    cisk13-trans:prostadienoic acid and the corresponding 11β-                    (Example 264)                                                            isomer                                                                        258  nat.-20-ethyl                                                                              nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-                      oxo-20-ethyl-5-                                                  prostaglandin A.sub.2                                                    cis,13-trans-prostadienoic acid and the corresponding 11β-                    (Example 263)                                                                              isomer                                                      259  erythro-16-hydroxy-                                                                        erythro-11α-(2-hydroxyethylthio)-15α,16-dihy                      droxy-9-oxo-5-                                                   prostaglandin A.sub.2                                                                      cis,13-trans-prostadienoic acid and the corresponding                         1β-                                                         (Example 277)                                                            isomer                                                                        260  threo-16-hydroxy                                                                           threo-11α-(2-hydroxyethylthio)-15α,16-dihydr                      oxy-9-oxo-5-cis,                                                 prostaglandin A.sub.2                                                                      13-trans-prostadienoic acid and the corresponding                             11β-isomer                                                  (Example 278)                                                            261  erythro-16-methoxy-                                                                        erythro-11α-(2-hydroxyethylthio)-15α-hydroxy                      -9-oxo-16-                                                  prostaglandin A.sub.2                                                         methoxy-5-cis,13-trans-prostadienoic acid and the                                  (Example 279)                                                                              corresponding 11β-isomer                               262  threo-16-methoxy-                                                                          threo-11α-(2-hydroxyethylthio)-15α-hydroxy-9                      -oxo-16-methoxy-                                            prostaglandin A.sub.2                                                         5-cis,13-trans-prostadienoic acid and the corresponding                            (Example 280)                                                                              11β-isomer                                             __________________________________________________________________________

EXAMPLE 263 Preparation of nat.-20-ethyl prostaglandin A₂

A solution ofnat.-20-ethyl-9-oxo-11α,15(S)-bis-(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadienoicacid [U.S. Pat. No. 2,150,361 (West Germany, 1972)] in tetrahydrofurancontaining 1.5 N hydrochloric acid is kept at ambient temperature for 70hours. The solution is flooded with saturated sodium chloride andextracted several times with ether. The combined extracts are washedwith water, dried with anhydrous magnesium sulfate and taken to drynessto afford the subject compound.

EXAMPLES 264-280

The prostaglandins E of the table below when treated in the manner ofExample 263 furnish the corresponding prostaglandins A.

                                      TABLE 29                                    __________________________________________________________________________    Example                                                                            Starting Prostaglandins E                                                                         Product Prostaglandins A                             __________________________________________________________________________    264  nat.-20-methylprostaglandin-E.sub.2.sup.a                                                         nat.-20-methylprostaglandin-A.sub.2                  265  nat.-prostaglandin-E.sub.3 - E.J. Corey,                                                          nat.-prostaglandin-A.sub.3                                et al. Journ. Amer. Chem. Soc., 93,                                           1490 (1971)                                                              266  prostaglandin-E.sub.2 - E.J. Corey, et                                                            dl-prostaglandin-A.sub.2                                  al., Journ. Amer. Chem. Soc., 91,                                             5675 (1969)                                                              267  nat. 16,16-trimethylene PGE.sub.1 methyl                                                          nat. 16,16-trimethylene PGA.sub.1 methyl ester            ester.sup.b                                                              268  nat. 16,16-trimethylene PGE.sub.2 methyl                                                          nat. 16,16-trimethylene PGA.sub.2 methyl ester            ester.sup.b                                                              269  nat. 16,16-trimethylene PGE.sub.2.sup.b                                                           nat. 16,16-trimethylene PGA.sub.2                    270  nat. 16,16-trimethylene PGE.sub.1.sup.b                                                           nat. 16,16-triemthylene PGA.sub.1                    271  nat. 16,16-trimethylene-20-methyl                                                                 nat. 16,16-trimethylene-20-methyl PGA.sub.2               PGE.sub.2.sup.b                                                          272  nat. 16,16-trimethylene-20-ethyl                                                                  nat. 16,16-trimethylene-20-ethyl PGA.sub.2                PGE.sub.2                                                                273  11α,16-dihydroxy-17-methyl-9-oxo-                                                           16-hydroxy-17-methyl-9-oxo-10,13-trans-              13-trans-prostenoic acid.sup.c                                                prostadienoic acid                                                            274  ethyl 11α, 16-dihydroxy-17-methyl-                                                          ethyl 16-hydroxy-17-methyl-9-oxo-10,13-trans-        9-oxo-13-trans-prostenoic acid.sup.c                                          prostadienoate                                                                275  11α,16-dihydroxy-9-oxo-13-trans-                                                            16-hydroxy-9-oxo-10,13-trans-prostadienoic acid      prostenoic acid.sup.c                                                         276  11α,16-dihydroxy-9-oxo-20-nor-13,17-                                                        16-hydroxy-9-oxo-20-nor-10,13-trans,17-trans-        trans,trans-prostadienoic acid.sup.c                                          prostadienoic acid                                                            277  crythro-11α,15α,16-trihydroxy-9-                                                      crythro-15α,16-dihydroxy-9-oxo-5-cis,10,13-                             trans-                                               oxo-5-cis,13-trans-prostadienoic                                              prostatrienoic acid                                                                acid.sup.d                                                               278  threo-11α,15α,16-trihydroxy-9-oxo-                                                    threo-15α,16-dihydroxy-9-oxo-5-cis,10,13-tr                             ans-                                                 5-cis,13-trans-prostadienoic acid.sup.d                                       prostatrienoic acid                                                           279  erythro-11α,15α-dihydroxy-16-methoxy-                                                 erythro-15α-hydroxy-9-oxo-16-methoxy-5-cis,                             10,13-                                               9-oxo-5-cis,13-trans-prostadienoic                                            trans-prostatrienoic acid                                                          acid.sup.e                                                               280  threo-11α,15α-dihydroxy-16-methoxy-                                                   threo-15α-hydroxy-9-oxo-16-methoxy-5-cis,10                             ,13-                                                 5-cis,13-trans-prostadienoic acid.sup.e                                       trans-prostatrienoic acid                                                     __________________________________________________________________________     .sup.a. D. van Dorp, Annal of the New York Academy of Sciences, Volume        180, 181 (1971).                                                              .sup.b. W. German Patent No. 2,510,818 (March 14, 1974).                      .sup.c. U. S. Patent No. 3,950,406 (April 12, 1976).                          .sup.d. Japan Patent No. J5 1008-249 (Derivent 1783ox110) (July 7, 1974).     .sup.e. Japan Patent No. J5 0070-340 (Derivent 61814w137) (October 29,        1973).                                                                   

EXAMPLE 281 Preparation of2-(6-carboxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one

To a stirred solution of 2.24 g. (10 mmols) of2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one (U.S. Pat. No.3,952,033) and 0.82 g (10.5 mmols) of β-mercaptoethanol in 50 ml ofmethanol is added 10.5 ml of N/1 sodium methoxide in methanol solutionduring 30 minutes at room temperature. After the addition the solutionis stirred at room temperature for 1 hour and treated with 4.8 g ofglacial acetic acid (80 mmols). The solution is concentrated to volumeof 10 ml, treated with 30 ml of brine, and extracted with ethyl acetate.The extract is washed with brine, dried over magnesium sulfate, andconcentrated.

The resulting residue is purified by column chromatography on silica gelwith chloroform progressively enriched in ether and finally ether toprovide an oil.

EXAMPLE 282 Preparation of Bis-Trimethylsilyl Derivative of2-(6-carboxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one

To a stirred, ice-cold solution of 1.42 g (5.0 mmols) of2-(6-carboxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)-cyclopent-2-en-1-one(Example 281) in 10 ml of pyridine is added 2.50 ml ofhexamethyldisilazane followed by 1.25 ml of chlorotrimethylsilane. Theresulting mixture is stirred at ambient temperature for 4 hours. Thevolatile materials are evaporated under vacuum, and the resultingresidue is stirred with petroleum ether. The mixture is filtered throughcelite, and the filtrate is concentrated to give a light yellow liquid.

EXAMPLE 283 Preparation of2-(6-carboxyhexyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one

In the manner of Example 281 a methanol solution of2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-1-one [Prostaglandins, 3, 921(1973)] and β-mercaptoethanol is treated with sodium methoxide solution,acidified, concentrated, and extracted to provide the subject compoundas an oil.

EXAMPLE 283a Preparation of Bis-Trimethylsilyl Derivative of2-(6-carboxyhexyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one

In the manner of Example 281a a solution of2-(6-carboxyhexyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one (Example282) in pyridine is treated with hexamethyldisilazane andchlorotrimethylsilane to provide the subject compound as a liquid.

EXAMPLE 284 Preparation of2-(6-carboxymethoxy-2-cis-hexenyl)-4-methoxycyclopent-2-en-1-one

A stirred solution of 6.28 g (27.8 mmols) of2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one (U.S. Pat. No.3,952,033) and 7.6 ml of concentrated sulfuric acid is heated at refluxtemperature for 40 hours. The solution is treated with 7.4 g of sodiumcarbonate, concentrated, and partitioned with ether-brine. The etherextract is washed with brine, dried over magnesium sulfate, andconcentrated. The resulting residue is distilled to provide a colorlessliquid, b.p. 130°-134° (0.05 mm).

EXAMPLE 285 Preparation of2-(6-carbomethoxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-on

To a stirred solution of 7.57 g (30 mmols) of2-(6-carbomethoxy-2-cis-hexenyl)-4-methoxycyclopent-2-en-1-one (Example283) and 2.46 g (31.5 mmols) of β-mercaptoethanol in 150 ml of methanolis added 15 ml of N/10 sodium methoxide in methanol solution. After 50minutes at room temperature the solution is acidified with 0.27 ml ofgl. acetic acid and partitioned with ether-brine. The ether extract iswashed with brine, dried over magnesium sulfate, and concentrated. Theresidue is subjected to column chromatography on silica-gel to providean oil.

EXAMPLE 286 Preparation of2-(6-carbomethoxy-2-cis-hexenyl)-4-(2-trimethylsiloxyethylthio)cyclopent-2-en-1-one

To a stirred, ice-cold solution of 2.98 g (10 mmols) of2-(6-carbomethoxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one(Example 283a) in 10 ml of pyridine is added 2.50 ml ofhexamethyldisilazane followed by 1.25 ml of chlorotrimethylsilane. Theresulting mixture is stirred at ambient temperature for 2.5 hours. Thevolatile materials are evaporated under vacuum, and the resultingresidue is stirred with petroleum ether. The mixture is filtered throughCelite, and the filtrate is concentrated to give a light yellow liquid.

EXAMPLE 287 Preparation of dl-methyl esters of11-deoxy-11α-(2-hydroxyethylthio)-15α-prostaglandin E₂ and the15β-isomer

To a stirred solution of 2.48 g (5.0 mmols) of1-iodo-3-triphenylmethoxy-trans-1-octene (Tetrahedron Letters, 1975,765) in 20 ml of ether at -78° is added 6.25 ml of 1.6 M t-butyllithiumin pentane during 10 minutes. The solution is stirred at -78° for 1hour, warmed to -45° during 15 minutes and recooled to -78°.

The above solution is treated during 10 minutes with a solution preparedfrom 653 mg (5.0 mmols) of copper pentyne, 2.1 ml ofhexamethylphosphorous triamide, and 15 ml of ether, at a temperature of-78° to -70°. The resulting solution is stirred at -78° for 60 minutesand treated during 10 minutes with a solution of 1.48 g (4.0 mmols) of2-(6-carbomethoxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one(Example 283b) in 10 ml of ether. After 10 minutes at -78° the solutionis warmed to -45° during 10 minutes, maintained at -45° to -40° for 2hours, recooled to -78°, and treated with a solution of 0.60 ml of gl.acetic acid in 10 ml of ether. The mixture is diluted with 100 ml ofether and poured into a stirred, ice-cold mixture of 50 ml of saturatedammonium chloride and 10 ml of 4 N hydrochloric acid. The ether phase isseparated and washed successively with cold 2 N hydrochloric acid,water, and brine. The solution is dried over magnesium sulfate andconcentrated.

The residue (3.24 g) is dissolved in a solution of 32 ml of gl. aceticacid, 16 ml of THF, and 8 ml of water, and the solution is heated at 45°for 6 hours and partitioned with half-saturated brine and ether. Theether phase is washed with brine, dried over magnesium sulfate, andconcentrated.

The residue is subjected to dry column chromatography on silica gel withthe solvent system 60:40:1 benzene-ethyl acetate-acetic acid to providethe more mobile epimer(11-deoxy-11α-(2-hydroxyethylthio)-15-epi-prostaglandin E₂,methyl ester)as a light yellow oil, and the more polar epimer(11-deoxy-11α-(2-hydroxyethylthio)-prostaglandin E₂,methyl ester) as alight yellow oil.

EXAMPLES 288-373

Treatment of ether cyclopentenone 282 or 283 with a lithio cuprategenerated from the indicated vinyl iodide of Table 30 by the proceduredescribed in Example 287 followed by chromatography is productive of theseparated 15-hydroxy epimers and 16-hydroxy mixtures. When avinylstannyl molecule is utilized, the lithiation is accomplished intetrahydrofuran with n-butyllithium (1. equiv.) at -40° to -20° C. for1-3 hours.

                                      TABLE 30                                    __________________________________________________________________________    Example                                                                            Starting Olefin                                                                         Starting Cyclopentenone                                                                   Separated Products                                 __________________________________________________________________________    288  13        282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-                                           16,16-trimethylene-5-cis,13-trans-prostadienoic                                                          acid and the 15β-epimer                       289  50        282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16,16-                                     trimethylene-20-methyl-5-cis,13-trans-prosta-                                                            dienoic acid and the 15β-epimer               290  51        282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16,16-                                     trimethylene-20-ethyl-5-cis,13-trans-prostadien-                                                         oic acid and the 15β-epimer                   291  194       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               vinyl-5-cis,13-trans-prostadienoic acid                                       292  192       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               cyclopropyl-5-cis,13-trans-prostadienoic acid                                 293  193       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               cyclopropyl-20-ethyl-5-cis,13-trans-prostadienoic                                                        acid                                               294  195       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               vinyl-20-ethyl-5-cis,13-trans-prostadienoic acid                              295  76        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .,16-di-                                                                      hydroxy-9-oxo-5-cis,13-trans-                      prostadienoic acid and the 15β-epimer                                    296  74        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .-hydroxy-9-                                       oxo-16-methoxy-5-cis,13-trans-prostadienoic                                                              acid and the 15β-epimer                       297  77        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .-hydroxy-9-                                       oxo-16-ethoxy-5-cis,13-trans-priostadienoic acid                                                         and the 15β-isomer                            298  84        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .,16-di-                                                                      hydroxy-9-oxo-20-methyl-5-cis,13-trans-prosta-                                J                                                                             dienoic acid and the 15β-epimer               299  85        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .,16-di-                                                                      hydroxy-9-oxo-20-ethyl-5-cis,13-trans-prosta-                                 dienoic acid and the 15β-epimer               300  87        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .,16-di-                                                                      hydroxy-9-oxo-5-cis,13-trans-17-trans-prosta-                                 trienoic acid and the 15β-epimer              301  69        282         threo-11α-(2-hydroxyethylthio)-15α,                               16-dihydroxy-                                      9-oxo-5-cis,13-trans-prostadienoic acid and                                                              the 15β-epimer                                302  89        282         threo-11α-(2-hydroxyethylthio)-15α,                               16-dihydroxy-                                      9-oxo-20-methyl-5-cis,13-trans-prostadienoic                                                             acid and the 15β-epimer                       303  90        282         threo-11α-(2-hydroxyethylthio)-15α,                               16-dihydroxy-                                      9-oxo-20-ethyl-5-cis,13-trans-prostadienoic                                                              acid and the 158β-isomer                      304  130       282         11α(2-hydroxyethylthio)-16-hydroxy-9-oxo-                               16-                                                methyl-6-cis,13-trans-prostadienoic acid                                      305  107       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -5-cis,                                                                       13-trans-prostadienoic acid                        306  144       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -17-                                               methyl-5-cis,13-trans-prostadienoic acid                                      307  112       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                               methyl-5-cis,13-trans-prostadienoic acid                                      308  113       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                               ethyl-5-cis,13-trans-prostadienoic acid                                       309  139a      282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               methyl-20-ethyl-5-cis,13-trans-prostadienoic                                                             acid                                               310  137       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16,20-                                            dimethyl-5-cis,13-trans-prostadienoic acid                                    311  139       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               methyl-5-cis,13-trans-17-trans-prostatrienoic                                                            acid                                               312  151       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -17-                                               methyl-20-ethyl-5-cis,13-trans-prostadienoic                                                             acid                                               313  152       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -5-cis,                                                                       13-trans-17-trans-prostatrienoic acid              314  153       282         11α-(2-hydroxyethylthio)-16(R)-hydroxy-9-                               oxo-                                               cis,13-trans-prostadienoic acid                                               315  154       282         11α-(2-hydroxyethylthio)-16(S)-hydroxy-9-                               oxo-5-                                             cis,13-trans-prostadienoic acid                                               316  148a      282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                               ethyl-5-cis,13-trans-17-trans-prostatrienoic                                                             acid                                               317  1-iodo-3-tri-                                                                           282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-5-                                              phenylmethoxy-1-                                                         cis,13-trans-prostadienoic acid and the 15β-                             trans-octene                                                                  epimer                                                                             (U.S. Pat. No.                                                                3,873,607).                                                              318  1-iodo-3-tri-                                                                           282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-20-                                             phenylmethoxy-1-                                                         methyl-5-cis,13-trans-prostadienoic acid and                                  trans-nonene   the 15β-epimer                                                 (U.S. Pat. No.                                                                3,873,607).                                                              319  1-iodo-3-tri-                                                                           282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-20-                                             phenylmethoxy-1-                                                         ethyl-5-cis,13-trans-prostadienoic acid and                                   trans-decene   the 15β-epimer                                                 (U.S. Pat. No.                                                                3,873,607).                                                              320  1-iodo-3-tri-                                                                           282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16,16-                                          phenylmethoxy-4,4-                                                       dimethyl-5-cis,13-trans-prostadienoic acid and                                dimethyl-1-trans-                                                                            the 15β-epimer                                            octene (U.S. Pat.                                                                  No. 3,873,607).                                                          321  1-iodo-3-tri-                                                                           282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16-                                             phenylmethoxy-4-                                                         methyl-5-cis,13-trans-prostadienoic acid and                                  methyl-1-trans-                                                                              the 15β-isomer                                            octene (U.S. Pat.                                                                  No. 3,876,690).                                                          322  1-iodo-3-tri-                                                                           282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16-                                             phenylmethoxy-4-                                                         ethyl-5-cis,13-trans-prostadienoic acid and                                   ethyl-1-trans- the 15β-epimer                                            octene (U.S. Pat.                                                                  No. 3,876,690).                                                          323  1-iodo-3-methyl-                                                                        282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-15-                                        3-trimethylsilyl-                                                             methyl-5-cis,13-trans-prostadienoic acid and                                       oxy-trans-1-octene    the 15β-epimer                                     (Example 185)                                                            324  1-iodo-3-methyl-3-                                                                      282         11α-(hydroxyethylthio)-15α-hydroxy-                               9-oxo-15-                                          trimethylsilyloxy-                                                            methyl-20-ethyl-5-cis,13-trans-prostadienoic                                  trans-1-decene acid and the 15β-epimer                                        (Example 190a)                                                           325  220       282         11α-(2-hydroxyethylthio)-15-hydroxy-9-oxo                               -15,19-                                            methylene-20-nor-5-cis,13-trans-prostadienoic                                                            acid                                               326  221       282         11α-(2-hydroxyethylthio)-15-hydroxy-9-oxo                               -15,18-                                            methylene-19,20-dinor-5-cis,13-trans-prostadien-                                                         oic acid and the 15β-epimer                   327  219       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16,20-                                            methylene-5-cis,13-trans-prostadienoic acid                                   328  222       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16,19-                                            methylene-20-nor-5-cis,13-trans-prostadienoic                                                            acid                                               329  216       282         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-15,16-                                     cis-trimethylene-5-cis,13-trans-prostadienoic                                                            acid and the 15β-epimer                       330  139a      282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                               ethyl-5-cis,13-trans-17-trans-prostatrienoic                                                             acid                                               331  13        283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16,16-                                     trimethylene-13-trans-prostenoic acid and the                                                            15β-epimer                                    332  50        283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16,16-                                     trimethylene-20-methyl-13-trans-prostenoic                                                               acid and th 15β-epimer                        333  51        283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16,16-                                     trimethylene-20-ethyl-13-trans-prostenoic acid                                                           and the 15β-epimer                            334  194       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               vinyl-13-trans-prostenoic acid                                                335  192       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               cyclopropyl-13-trans-prostenoic acid                                          336  193       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               cyclopropyl-20-ethyl-13-trans-prostenoic acid                                 337  195       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                               vinyl-20-ethyl-13-trans-prostenoic acid                                       338  76        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .,16-di-                                                                      hydroxy-9-oxo-13-trans-prostenoic acid and                                    the                                                                           15β-epimer                                    339  74        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .-hydroxy-9-                                                                  oxo-16-methoxy-13-trans-prosteoic acid and                                    the                                                                           15β-epimer                                    340  77        283         erythro-11α-(2-hydroxyethylthio)-16.alpha                               .-hydroxy-9-                                                                  oxo-16-ethoxy-13-trans-prostenoic acid and                                    the                                                               15β-isomer                                                341  84        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                               .,16-dihydroxy-                                                               9-oxo-20-methyl-13-trans-prostenoic acid and                                  the 15β-epimer                                342  85        283         erythro-11α-(2-hydroxyethylthio)-15═,                               16-dihydroxy-                                                                 9-oxo-20-ethyl-13-trans-prostenoic acid and                                   the                                                                           15β-epimer                                    343  87        283         erythro-11α-(2-hydroxyethylthio)-15β                               ,16-dihydroxy-                                                                9-oxo-13-trans-17-trans-prostadienoic acid                                    and                                                                           the 15β-epimer                                344  69        283         threo-11α-(2-hydroxyethylthio)-15α,                               16-dihydroxy-                                                                 9-oxo-13-trans-prostenoic acid and the                                        15β-epimer                                    345  89        283         threo-11α-(2-hydroxyethylthio)-15α,                               16-dihydroxy-                                                                 9-oxo-20-methyl-13-trans-prostenoic acid and                                  the                                                                           15β-epimer                                    346  90        283         threo-11α-(2-hydroxyethylthio)-15α,                               16-dihydroxy-                                                                 9-oxo-20-ethyl-13-trans-prostenoic acid and                                   the                                                                           15β-isomer                                    347  130       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                                                          methyl-13-trans-prostenoic acid                    348  107       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -13-                                                                          trans-prostenoic acid                              349  144       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -17-                                                                          methyl-13-trans-prostenoic acid                    350  112       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                                                          methyl-13-trans-prostenoic acid                    351  113       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                                                          ethyl-13-trans-prostenoic acid                     352  139a      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                                                          methyl-20-ethyl-13-trans-prostenoic acid           353  137       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16,20-                                                                       dimethyl-13-trans-prostenoic acid                  354  139       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                                                          methyl-13-trans-17-trans-prostadienoic acid        355  151*      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -17-                                                                          methyl-20-ethyl-13-trans-prostenoic acid           356  152       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -13-                                                                          trans-17-trans-prostadienoic acid                  357  153       283         11α-(2-hydroxyethylthio)-16(R)-hydroxy-9-                               oxo-13-                                                                       trans-prostenoic acid                              358  154       283         11α-(2-hydroxyethylthio)-16(S)-hydroxy-9-                               oxo-13-                                                                       trans-prostenoic acid                              359  148a      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                                                          ethyl-13-trans-17-trans-prostadienoic acid         353  137       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16,20-                                                                       dimethyl-13-trans-prostenoic acid                  354  139       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16-                                                                          methyl-13-trans-17-trans-prostadienoic acid        355  151*      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -17-                                                                          methyl-20-ethyl-13-trans-prostenoic acid           356  152       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -13-                                                                          trans-17-trans-prostadienoic acid                  357  153       283         11α-(2-hydroxyethylthio)-16(R)-hydroxy-9-                               oxo-13-                                                                       trans-prostenoic acid                              358  154       283         11α-(2-hydroxyethylthio)-16(S)-hydroxy-9-                               oxo-13-                                                                       trans-prostenoic acid                              359  148a      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                                                          ethyl-13-trans-17-trans-prostadienoic acid         360  1-iodo-3-tri-                                                                           283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-13-                                             phenylmethoxy-1-      trans-prostenoic acid and the 15β-epimer           trans-octene                                                                  (U.S. Pat. No.                                                                3,873,607).                                                              362  1-iodo-3-tri-                                                                           283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-20-                                             phenylmethoxy-1-      ethyl-13-trans-prostenoic acid and the                                        15β-                                               trans-decene          epimer                                                  (U.S. Pat. No.                                                                3,873,607).                                                              363  1-iodo-3-tri-                                                                           283         11α-(2-hydroxyethylthio-15α-hydroxy                               -9-oxo-16,16-                                           phenylmethoxy-4,4-    dimethyl-13-trans-prostenoic acid and the                                     15β-                                               dimethyl-1-trans-     epimer                                                  octene (U.S. Pat.                                                             No. 3873,607).                                                           364  1-iodo-3-tri-                                                                           283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16-                                             phenylmethoxy-4-      methyl-13-trans-prostenoic acid and the                                       15β-                                               methyl-1-trans-       isomer                                                  octene (U.S. Pat.                                                             No. 3876,690).                                                           365  1-iodo-3-tri-                                                                           283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-16-                                             phenylmethoxy-4-      ethyl-13-trans-prostenoic acid and the                                        15β-                                               ethyl-1-trans-        epimer                                                  octene (U.S. Pat.                                                             No. 3,876,690).                                                          366  1-iodo-3-methyl-                                                                        283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-15-                                             3-trimethylsilyl-     methyl-13-trans-prosteoic acid and the                                        15β-                                               oxy-trans-1-octene    epimer                                                  (Example 190)                                                            367  1-iodo-3-methyl-                                                                        283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-                                                3-trimethylsilyl-     15-methyl-20-ethyl-13-trans-prostenoic acid             oxy-trans-1-decene    and the 15β-epimer                                 (Example 190a)                                                           368  220       283         11α-(2-hydroxyethylthio)-15-hydroxy-9-oxo                               -15,19-                                                                       methylene-20-nor-13-trans-prostenoic acid          369  221       283         11α-(2-hydroxyethylthio)-15-hydroxy-9-oxo                               -15,18-                                                                       methylene-19,20-dinor-13-trans-prostenoic                                     acid                                                                          and the 15β-epimer                            370  219       283         11α-(2-hydroxyethylthio)-16-hyroxy-9-oxo-                               16,20-                                                                        methylene-13-trans-prostenoic acid                 371  222       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -16,19- -   methylene-20-nor-13-trans-prostenoi                               c acid                                             372  216       283         11α-(2-hydroxyethylthio)-15α-hydrox                               y-9-oxo-15,16-                                                                cis-trimethylene-13-trans-prostenoic acid and                                 the 15β-epimer                                373  139a      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                               -20-                                                                          ethyl-13-trans-17-trans-prostadienoic              __________________________________________________________________________                               acid                                           

EXAMPLE 374 Preparation of 1R,2R(and1S,2S)-1-(trans-2-Iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 12.22 g of sodium borohydride and 60.82 g of2-methyl-2-butene in 450 ml of tetrahydrofuran under nitrogen at 0° C.,is added 54.6 ml of boron trifluoride etherate, dropwise over a 20minute period. The solution is stirred at 0° C. for 2 hours and then atroom temperature for 30 minutes. This solution is cooled to 0° C. and55.5 g of 1R,2R(and1S,2S)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 50 ml oftetrahydrofuran is added. The mixture is allowed to stand in a cold roomovernight. To this mixture at 0° C. is added with stirring 112.8 g oftrimethylamine oxide over a 20 minute period. The mixture is stirred atroom temperature for 90 minutes and then filtered. To the filtrate isadded simultaneously a solution of 565 g of sodium hydroxide in 2000 mlof water and a solution of 300 g of iodine in 300 ml of tetrahydrofuran.The mixture is stirred 30 minutes, the organic layer is separated andthe aqueous layer is extracted with ether. The combined organicsolutions are washed with saturated sodium thiosulfate solution and withsaturated sodium chloride solution. The solution is dried with magnesiumsulfate and filtered through a pad of silica gel. The solution isremoved giving an orange liquid which is chromatographed on a dry columnof silica gel giving 59.5 g of the product as a yellow liquid.

EXAMPLE 375 Preparation of1-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane

To a stirred mixture of 31.5 g of1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg ofazobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. Thestirred mixture is heated to about 80° C. The initial exothermicmaintained at 130°-135° C. for one hour.

The product is distilled to afford 56 g of colorless liquid, bp150°-160° C. (0.15-0.3 mm), pmr (CDCl₃): 6.0 (multiplet, vinyl protons).

EXAMPLE 376 Preparation of 4-Oxo-1-iodo-trans-1-octene

To a stirred suspension of 6.15 g of pyridinium chlorochromate(Tetrahedron Letters, 1975, 2647) in 20 ml of methylene chloride isadded 450 mg of sodium acetate. After 5 minutes a solution of 3.64 g of4-hydroxy-1-iodo-trans-1-octene in 15 ml of methylene chloride is addedin one portion. The dark mixture is stirred at room temperature for 75minutes, diluted with 50 ml of ether, and decanted. The solid sludge iswashed repeatedly with ether and decanted. The combined solutions arepercolated through Florisil. The solution is concentrated to give anorange liquid, pmr spectrum (CDCl₃): 3.20 (d, j=7 cps, ═CHCH₂ CO).

EXAMPLE 377 Preparation of 4Hydroxy-4-vinyl-1-iodo-trans-1-octene

To a stirred solution of 7.8 ml of vinyl magnesium chloride (2.3 M intetrahydrofuran), at -25° C. is added a solution of 3.55 g of4-oxo-1-iodo-trans-1-octene in 20 ml of tetrahydrofuran during 15minutes. After the addition, the solution is stirred at -20° C. to -15°C. for 30 minutes. The reaction is quenched with a mixture of hexane andice. The aqueous phase is separated and extracted with additionalhexane. The combined hexane extracts are washed successively with waterand brine. The solution is dried over magnesium sulfate andconcentrated. The residue is subjected to dry column chromatography onsilica gel with benzene as developing solvent to give a liquid, pmrspectrum (CDCl3): 5.2 (m, terminal CH₂), 5.83 (q, CH═CH₂), 6.13 (d,ICH═), and 6.52 (m, ICM═CH).

EXAMPLE 378 Preparation of E-1-Tri-n-butylstannyl-1-octene

A solution of 10.0 g (0.0908 mol) of 1-octyne, 60 ml of anhydroustoluene, 230 mg of azobisisobutylonitrile (AIBN), and 25 ml (0.0943 mol)of tri-n-butyltin hydride is refluxed under an argon atmosphere for 3hours. The reaction mixture is cooled to ambient temperature andconcentrated in vacuo. The resulting yellow liquid is distilled (bulb tobulb) to give 36.29 (99%) of the stannyl octene as a pale yellow liquid.

EXAMPLE 379 Preparation ofdl-11,15-Bisdeoxy-11α-(2-hydroxyethylthio)-PGE₂ methyl ester C-13,14 cisisomer

To a stirred solution of 4.49 (0.0054 mol) of vinyl stannane and 12 mlof anhydrous tetrahydrofuran, cooled to -78° C. is slowly added 5.2 ml(0.0114 mol) of n-butyllithium. After 15 minutes, the reaction mixtureis warmed to -15° C. for 11/2 hour, recooled to -78° C., and to it isadded a solution of 1.70 g (0.0130 mol) of copper (I) pentyne, 7 ml ofhexamethylphosphorous triamide (HMPTA), and 20 ml of anhydrous ether.After 1 hour, a solution of 2.0 g (0.00054 mol) of cyclopentenone 15 and15 ml of anhydrous ether is added. The resulting solution is stirred atthis temperature for 30 minutes, warmed to -30° C. for 2 hours, recooledto -78° C., and to it is added 5 ml of glacial acetic acid. The reactionmixture is poured into a saturated solution of ammonium chloride and isvigorously stirred for 30 minutes. The aqueous phase is separated andextracted with 150 ml of ether in 2 portions. The combined organicphases are washed with 5% hydrochloric acid solution and brine, and thenconcentrated in vacuo to give an amber oil. A solution of the oil in 140ml of acetic acid - tetrahydrofuran-water (4:2:1) is stirred at ambienttemperature for 1 hour, diluted with toluene, and concentrated in vacuoto give 6.1 g of amber oil. This oil is applied to a silica-gel drycolumn (3"×55"; 2:3 / ethyl acetate: benzene+2% acetic acid; and 600 mlof eluant is collected).

The more polar isomer (13-cis) is isolated from the column at R_(f)0.58-0.65 as 133 mg (6%) of a yellow oil.

The less polar isomer (13-trans) is isolated from the column at R_(f)0.73-0.81 as 951 mg (43%) of a yellow oil.

We claim:
 1. An optically active compound of the formula: ##STR43##wherein Z is a divalent moiety selected from the group consisting of--(CH₂)₆ -- and ##STR44## R₁ is selected from the group consisting ofhydroxy and C₁ -C₆ alkoxy; and R is a moiety selected from the groupconsisting of ##STR45## wherein R₆ is selected from the group consistingof C₁ -C₂ alkyl, R₈ is selected from the group consisting of C₁ -C₂alkyl and R₁₁ is selected from the group consisting of C₃ -C₇ alkyl; theracemic mixture thereof; the mirror image thereof; and when R₁ ishydroxy, the pharmaceutically acceptable salts thereof.
 2. An opticallyactive compound according to claim 1, wherein Z, R and R₁ are aspreviously defined; and the substituent at the carbon-11 position isβ-(2-hydroxyethylthio).
 3. An optically active compound according toclaim 1, wherein Z, R and R₁ are as previously defined; and thesubstituent at the carbon-11 position is α-(2-hydroxyethylthio).
 4. Anoptically active compound according to claim 3, wherein R₁ and Z are aspreviously defined; and R is a moiety selected from the group consistingof ##STR46## wherein R₁₁ is as previously defined.
 5. An opticallyactive compound according to claim 3, wherein R₁ and Z are as previouslydefined; and R is a moiety selected from the group consisting of##STR47## wherein R₆ and R₈ are as previously defined.
 6. The racemiccompound according to claim 2, threodl-11β-(2-hydroxyethylthio)-15α,16-dihydroxy-9-oxo-5-cis,13-trans-prostadienoicacid.
 7. The racemic compound according to claim 2, erythrodl-11β-(2-hydroxyethylthio)-15α,16-dihydroxy-9-oxo-5-cis,13-trans-prostadienoicacid.
 8. The racemic compound according to claim 4, threodl-11α-(2-hydroxyethylthio)-15α,16-dihydroxy-9-oxo-5-cis,13-trans-prostadienoicacid.
 9. The racemic compound according to claim 4, erythrodl-11α-(2-hydroxyethylthio)-15α,16-dihydroxy-9-oxo-5-cis,13-trans-prostadienoicacid.
 10. The racemic compound according to claim 4, threodl-11α-(2-hydroxyethylthio)-15α,16-dihydroxy-9-oxo-13-trans-prostenoicacid.
 11. The racemic compound according to claim 4, erythrodl-11α-(2-hydroxyethylthio)-15α,16-dihydroxy-9-oxo-13-trans-prostenoicacid.